Journal articles on the topic 'Cardiomyocytes'
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1
Nguyen, Phong D., Sarah T. Hsiao, Priyadharshini Sivakumaran, Shiang Y. Lim, and Rodney J. Dilley. "Enrichment of neonatal rat cardiomyocytes in primary culture facilitates long-term maintenance of contractility in vitro." American Journal of Physiology-Cell Physiology 303, no. 12 (December 15, 2012): C1220—C1228. http://dx.doi.org/10.1152/ajpcell.00449.2011.
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Long-term culture of primary neonatal rat cardiomyocytes is limited by the loss of spontaneous contractile phenotype within weeks in culture. This may be due to loss of contractile cardiomyocytes from the culture or overgrowth of the non-cardiomyocyte population. Using the mitochondria specific fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), we showed that neonatal rat cardiomyocytes enriched by fluorescence-activated cell sorting can be maintained as contractile cultures for long periods (24-wk culture vs. 2 wk for unsorted cardiomyocytes). Long-term culture of this purified cardiomyocyte (TMRM high) population retained the expression of cardiomyocyte markers, continued calcium cycling, and displayed cyclic electrical activity that could be regulated pharmacologically. These findings suggest that non-cardiomyocyte populations can negatively influence contractility of cardiomyocytes in culture and that by purifying cardiomyocytes, the cultures retain potential as an experimental model for longitudinal studies of cardiomyocyte biology in vitro.
2
Derks, Wouter, and Olaf Bergmann. "Polyploidy in Cardiomyocytes." Circulation Research 126, no. 4 (February 14, 2020): 552–65. http://dx.doi.org/10.1161/circresaha.119.315408.
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The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and regeneration.
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Zhang, Yidi, Xin Zhao, and Yaowei Liu. "A visual detection method of cardiomyocyte relaxation and contraction." AIP Advances 13, no. 2 (February 1, 2023): 025028. http://dx.doi.org/10.1063/5.0133456.
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Contraction and relaxation are important functions of cardiomyocytes, and measuring their characteristics provides an evaluation index to explore the effects of drugs on cardiomyocytes. In addition, cardiomyocytes have an innate advantage in acting as a biopower by virtue of their ability to contract and relax, which also requires the detection of cardiomyocyte actions. However, existing measurement methods, such as mechanosensor measurements and calcium concentration measurements, have high requirements for experimental equipment and operation and are challenging to perform simultaneously with other cellular manipulations. Here, we propose a simple visual detection method for cardiomyocyte contraction and relaxation. We first recorded the contraction and relaxation of cardiomyocytes under a bright-field microscope, then used the optical flow method to track the sampling points on the cardiomyocytes in the video, and obtained the frequency of cardiomyocyte contraction and relaxation by analyzing the optical flow matrices. This method does not require the use of additional equipment or additional processing of cardiomyocytes, which significantly reduces the operational difficulty of detection and provides a method to achieve real-time detection of cardiomyocyte contraction and relaxation.
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Lieben Louis, Xavier, Pema Raj, Zach Meikle, Liping Yu, Shannel E. Susser, Shayla MacInnis, Todd A. Duhamel, Jeffrey T. Wigle, and Thomas Netticadan. "Resveratrol prevents palmitic-acid-induced cardiomyocyte contractile impairment." Canadian Journal of Physiology and Pharmacology 97, no. 12 (December 2019): 1132–40. http://dx.doi.org/10.1139/cjpp-2019-0051.
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Long-chain saturated fatty acids, especially palmitic acid (PA), contribute to cardiomyocyte lipotoxicity. This study tests the effects of PA on adult rat cardiomyocyte contractile function and proteins associated with calcium regulating cardiomyocyte contraction and relaxation. Adult rat cardiomyocytes were pretreated with resveratrol (Resv) and then treated with PA. For the reversal study, cardiomyocytes were incubated with PA prior to treatment with Resv. Cardiomyocyte contractility, ratio of rod- to round-shaped cardiomyocytes, and Hoechst staining were used to measure functional and morphological changes in cardiomyocytes. Protein expression of sarco-endoplasmic reticulum ATPase 2a (SERCA2a), native phospholamban (PLB) and phosphorylated PLB (pPLB ser16 and pPLB thr17), and troponin I (TnI) and phosphorylated TnI (pTnI) were measured. SERCA2a activity was also measured. Our results show that PA (200 μM) decreased the rate of cardiomyocyte relaxation, reduced the number of rod-shaped cardiomyocytes, and increased the number of cells with condensed nuclei; pre-treating cardiomyocytes with Resv significantly prevented these changes. Post-treatment with Resv did not reverse morphological changes induced by PA. Protein expression levels of SERCA2a, PLB, pPLBs, TnI, and pTnI were unchanged by PA or Resv. SERCA2a activity assay showed that Vmax and Iono ratio were increased with PA and pre-treatment with Resv prevented this increase. In conclusion, our results show that Resv protect cardiomyocytes from contractile dysfunction induced by PA.
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Stopp, Sabine, Marco Gründl, Marc Fackler, Jonas Malkmus, Marina Leone, Ronald Naumann, Stefan Frantz, et al. "Deletion of Gas2l3 in mice leads to specific defects in cardiomyocyte cytokinesis during development." Proceedings of the National Academy of Sciences 114, no. 30 (July 11, 2017): 8029–34. http://dx.doi.org/10.1073/pnas.1703406114.
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GAS2L3 is a recently identified cytoskeleton-associated protein that interacts with actin filaments and tubulin. The in vivo function of GAS2L3 in mammals remains unknown. Here, we show that mice deficient in GAS2L3 die shortly after birth because of heart failure. Mammalian cardiomyocytes lose the ability to proliferate shortly after birth, and further increase in cardiac mass is achieved by hypertrophy. The proliferation arrest of cardiomyocytes is accompanied by binucleation through incomplete cytokinesis. We observed that GAS2L3 deficiency leads to inhibition of cardiomyocyte proliferation and to cardiomyocyte hypertrophy during embryonic development. Cardiomyocyte-specific deletion of GAS2L3 confirmed that the phenotype results from the loss of GAS2L3 in cardiomyocytes. Cardiomyocytes fromGas2l3-deficient mice exhibit increased expression of a p53-transcriptional program including the cell cycle inhibitor p21. Furthermore, loss of GAS2L3 results in premature binucleation of cardiomyocytes accompanied by unresolved midbody structures. Together these results suggest that GAS2L3 plays a specific role in cardiomyocyte cytokinesis and proliferation during heart development.
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Mensah, Isaiah K., and Humaira Gowher. "Signaling Pathways Governing Cardiomyocyte Differentiation." Genes 15, no. 6 (June 18, 2024): 798. http://dx.doi.org/10.3390/genes15060798.
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Cardiomyocytes are the largest cell type that make up the heart and confer beating activity to the heart. The proper differentiation of cardiomyocytes relies on the efficient transmission and perception of differentiation cues from several signaling pathways that influence cardiomyocyte-specific gene expression programs. Signaling pathways also mediate intercellular communications to promote proper cardiomyocyte differentiation. We have reviewed the major signaling pathways involved in cardiomyocyte differentiation, including the BMP, Notch, sonic hedgehog, Hippo, and Wnt signaling pathways. Additionally, we highlight the differences between different cardiomyocyte cell lines and the use of these signaling pathways in the differentiation of cardiomyocytes from stem cells. Finally, we conclude by discussing open questions and current gaps in knowledge about the in vitro differentiation of cardiomyocytes and propose new avenues of research to fill those gaps.
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Zhang, Jun, Yuying Gao, Peng Chen, Yu Zhou, Sheng Guo, Li Wang, and Jie Chen. "Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Exosome Carrying MiRNA-312 Inhibits Sevoflurane-Induced Cardiomyocyte Apoptosis Through Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway." Journal of Biomaterials and Tissue Engineering 12, no. 5 (May 1, 2022): 947–52. http://dx.doi.org/10.1166/jbt.2022.2971.
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This study was to explore the mechanism by how exosomes (exo) derived from BMSCs affects cardiomyocyte apoptosis. BMSCs were isolated and incubated with cardiomyocytes while the cardiomyocytes were exposed to sevoflurane or DMSO treatment. Apoptotic cells were calculated and level of apoptosis related proteins was detected by Western blot. Through transfection with microRNA-(miRNA)-312 inhibitor, we evaluated the effect of BMSC-exo on the sevoflurane-induced apoptosis. Sevoflurane significantly inhibited the viability of cardiomyocytes and induced cardiomyocyte apoptosis. Besides, sevoflurane decreased the expression of miR-312 and enhanced Bax expression in cardiomyocytes through restraining the phosphorylation of MAPK/ERK. Treatment with BMSC-exo, however, activated MAPK/ERK signaling by up-regulating miR-312, thereby inhibiting cardiomyocyte apoptosis, promoting cardiomyocyte proliferation, and elevating the level of Bcl-2. In conclusion, BMSC-exo-derived miR-312 inhibits sevoflurane-induced cardiomyocyte apoptosis by activating PI3K/AKT signaling pathway.
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Chiu, Chiung-Zuan, Bao-Wei Wang, Tun-Hui Chung, and Kou-Gi Shyu. "Angiotensin II and the ERK pathway mediate the induction of myocardin by hypoxia in cultured rat neonatal cardiomyocytes." Clinical Science 119, no. 7 (June 22, 2010): 273–82. http://dx.doi.org/10.1042/cs20100084.
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Hypoxic injury to cardiomyocytes is a stress that causes cardiac pathology through cardiac-restricted gene expression. SRF (serum-response factor) and myocardin are important for cardiomyocyte growth and differentiation in response to myocardial injuries. Previous studies have indicated that AngII (angiotensin II) stimulates both myocardin expression and cardiomyocyte hypertrophy. In the present study, we evaluated the expression of myocardin and AngII after hypoxia in regulating gene transcription in neonatal cardiomyocytes. Cultured rat neonatal cardiomyocytes were subjected to hypoxia, and the expression of myocardin and AngII were evaluated. Different signal transduction pathway inhibitors were used to identify the pathway(s) responsible for myocardin expression. An EMSA (electrophoretic mobility-shift assay) was used to identify myocardin/SRF binding, and a luciferase assay was used to identify transcriptional activity of myocardin/SRF in neonatal cardiomyocytes. Both myocardin and AngII expression increased after hypoxia, with AngII appearing at an earlier time point than myocardin. Myocardin expression was stimulated by AngII and ERK (extracellular-signal-regulated kinase) phosphorylation, but was suppressed by an ARB (AngII type 1 receptor blocker), an ERK pathway inhibitor and myocardin siRNA (small interfering RNA). AngII increased both myocardin expression and transcription in neonatal cardiomyocytes. Binding of myocardin/SRF was identified using an EMSA, and a luciferase assay indicated the transcription of myocardin/SRF in neonatal cardiomyocytes. Increased BNP (B-type natriuretic peptide), MHC (myosin heavy chain) and [3H]proline incorporation into cardiomyocytes was identified after hypoxia with the presence of myocardin in hypertrophic cardiomyocytes. In conclusion, hypoxia in cardiomyocytes increased myocardin expression, which is mediated by the induction of AngII and the ERK pathway, to cause cardiomyocyte hypertrophy. Myocardial hypertrophy was identified as an increase in transcriptional activities, elevated hypertrophic and cardiomyocyte phenotype markers, and morphological hypertrophic changes in cardiomyocytes.
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Takaoka, Nanako, Michiko Yamane, Ayami Hasegawa, Koya Obara, Kyoumi Shirai, Ryoichi Aki, Hiroyasu Hatakeyama, et al. "Rat hair-follicle-associated pluripotent (HAP) stem cells can differentiate into atrial or ventricular cardiomyocytes in culture controlled by specific supplementation." PLOS ONE 19, no. 1 (January 26, 2024): e0297443. http://dx.doi.org/10.1371/journal.pone.0297443.
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There has been only limited success to differentiate adult stem cells into cardiomyocyte subtypes. In the present study, we have successfully induced beating atrial and ventricular cardiomyocytes from rat hair-follicle-associated pluripotent (HAP) stem cells, which are adult stem cells located in the bulge area. HAP stem cells differentiated into atrial cardiomyocytes in culture with the combination of isoproterenol, activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF), and cyclosporine A (CSA). HAP stem cells differentiated into ventricular cardiomyocytes in culture with the combination of activin A, BMP4, bFGF, inhibitor of Wnt production-4 (IWP4), and vascular endothelial growth factor (VEGF). Differentiated atrial cardiomyocytes were specifically stained for anti-myosin light chain 2a (MLC2a) antibody. Ventricular cardiomyocytes were specially stained for anti-myosin light chain 2v (MLC2v) antibody. Quantitative Polymerase Chain Reaction (qPCR) showed significant expression of MLC2a in atrial cardiomyocytes and MLC2v in ventricular cardiomyocytes. Both differentiated atrial and ventricular cardiomyocytes showed characteristic waveforms in Ca2+ imaging. Differentiated atrial and ventricular cardiomyocytes formed long myocardial fibers and beat as a functional syncytium, having a structure similar to adult cardiomyocytes. The present results demonstrated that it is possible to induce cardiomyocyte subtypes, atrial and ventricular cardiomyocytes, from HAP stem cells.
10
Shi, Huairui, Xuehong Zhang, Zekun He, Zhiyong Wu, Liya Rao, and Yushu Li. "Metabolites of Hypoxic Cardiomyocytes Induce the Migration of Cardiac Fibroblasts." Cellular Physiology and Biochemistry 41, no. 1 (2017): 413–21. http://dx.doi.org/10.1159/000456531.
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Background: The migration of cardiac fibroblasts to the infarct region plays a major role in the repair process after myocardial necrosis or damage. However, few studies investigated whether early hypoxia in cardiomyocytes induces the migration of cardiac fibroblasts. The purpose of this study was to assess the role of metabolites of early hypoxic cardiomyocytes in the induction of cardiac fibroblast migration. Methods: Neonatal rat heart tissue was digested with a mixture of trypsin and collagenase at an appropriate ratio. Cardiomyocytes and cardiac fibroblasts were cultured via differential adhesion. The cardiomyocyte cultures were subjected to hypoxia for 2, 4, 6, 8, 10, and 12 h. The supernatants of the cardiomyocyte cultures were collected to determine the differences in cardiac fibroblast migration induced by hypoxic cardiomyocyte metabolites at various time points using a Transwell apparatus. Meanwhile, ELISA was performed to measure TNF-α, IL-1β and TGF-β expression levels in the cardiomyocyte metabolites at various time points. Results: The metabolites of hypoxic cardiomyocytes significantly induced the migration of cardiac fibroblasts. The induction of cardiac fibroblast migration was significantly enhanced by cardiomyocyte metabolites in comparison to the control after 2, 4, and 6 h of hypoxia, and the effect was most significant after 2 h. The expression levels of TNF-α, IL-1β, IL-6, and TGF-β were substantially increased in the metabolites of cardiomyocytes, and neutralization with anti-TNF-α and anti-IL-1β antibodies markedly reduced the induction of cardiac fibroblast migration by the metabolites of hypoxic cardiomyocytes. Conclusion: The metabolites of early hypoxic cardiomyocytes can induce the migration of cardiac fibroblasts, and TNF-α and IL-1β may act as the initial chemotactic inducers.
11
Aix, Esther, Óscar Gutiérrez-Gutiérrez, Carlota Sánchez-Ferrer, Tania Aguado, and Ignacio Flores. "Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation." Journal of Cell Biology 213, no. 5 (May 30, 2016): 571–83. http://dx.doi.org/10.1083/jcb.201510091.
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The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc−/−) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc−/− newborns but rescued in G3 Terc−/−/p21−/− mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts.
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Goh, Joanna M., Jonathan G. Bensley, Kelly Kenna, Foula Sozo, Alan D. Bocking, James Brien, David Walker, Richard Harding, and M. Jane Black. "Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 2 (February 2011): H645—H651. http://dx.doi.org/10.1152/ajpheart.00689.2010.
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Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ∼145 days); tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability.
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Durham, Kristina K., Kevin M. Chathely, and Bernardo L. Trigatti. "High-density lipoprotein protects cardiomyocytes against necrosis induced by oxygen and glucose deprivation through SR-B1, PI3K, and AKT1 and 2." Biochemical Journal 475, no. 7 (April 5, 2018): 1253–65. http://dx.doi.org/10.1042/bcj20170703.
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The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD-induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1−/− mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes.
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Du, Meijiao, Zhengmei Wang, Geng Su, Yunxia Zhou, and Chuan Luo. "Exosomes Derived from Bone Marrow Mesenchymal Stem Cells (BMSC) Inhibit Apoptosis Factors Caspase-3 and Caspase-9 to Promote the Repair of Cardiomyocytes." Journal of Biomaterials and Tissue Engineering 11, no. 10 (October 1, 2021): 1990–95. http://dx.doi.org/10.1166/jbt.2021.2793.
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This study assesses the effect of exosomes derived from bone marrow mesenchymal stem cells (MSCs) on cardiomyocytes by inhibiting the apoptotic factors Caspase-3 and Caspase-9. Cell purity was evaluated under a microscope and exosomes were obtained by ultracentrifugation from the culture supernatant of BMSCs. Tunable resistive pulse sensing (TRPS) method analyzed the concentration distribution of exosomes particle size, and specific surface antigens were examined by flow cytometry. Exosomes were used to process cardiomyocytes to detect cardiomyocyte repair. After plasmid interference technology, the effect of exosomes on caspase-3 and caspase-9 expression was detected by western blot. The activity of cardiomyocytes was analyzed by CCK-8. Exosomes can promote the viability of cardiomyocytes. The mRNA and protein levels of GLUT3 in cardiomyocytes were significantly increased. Exosomes can inhibit cardiomyocyte apoptosis by down-regulating the expression of apoptosis-related proteins. Exosomes can improve the function and promote the repair of myocardium by inhibiting the expression of apoptotic factors Caspase-3 and Caspase-9.
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Cortes-Lopez, Fabiola, Alicia Sanchez-Mendoza, David Centurion, Luz G. Cervantes-Perez, Vicente Castrejon-Tellez, Leonardo del Valle-Mondragon, Elizabeth Soria-Castro, et al. "Fenofibrate Protects Cardiomyocytes from Hypoxia/Reperfusion- and High Glucose-Induced Detrimental Effects." PPAR Research 2021 (January 9, 2021): 1–15. http://dx.doi.org/10.1155/2021/8895376.
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Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.
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Shi, Xun, Xiaoli Tang, Fang Yao, Le Wang, Mingzhi Zhang, Xin Wang, Guangxin Yue, Li Wang, Shengshou Hu, and Bingying Zhou. "Isolation of porcine adult cardiomyocytes: Comparison between Langendorff perfusion and tissue slicing-assisted enzyme digestion." PLOS ONE 18, no. 5 (May 26, 2023): e0285169. http://dx.doi.org/10.1371/journal.pone.0285169.
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Tissue slicing-assisted digestion (TSAD) of adult cardiomyocytes has shown significant improvements over conventional chunk methods. However, it remains unclear how this method compares to Langendorff perfusion, the current standard of adult cardiomyocyte isolation. Using adult Bama minipigs, we performed cardiomyocyte isolation via these two distinct methods, and compared the resulting cellular quality, including viability, cellular structure, gene expression, and electrophysiological properties, of cardiomyocytes from 3 distinct anatomical regions, namely the left ventricle, right ventricle, and left atrial appendage. Our results revealed largely indistinguishable cell quality in all of the measured parameters. These findings suggest that that TSAD can be reliably used to isolate adult mammalian cardiomyocytes as a reliable alternative to perfusion in cardiomyocyte isolation from larger mammals, particularly when Langendorff perfusion is not feasible.
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Mensah, Isaiah K., and Humaira Gowher. "Epigenetic Regulation of Mammalian Cardiomyocyte Development." Epigenomes 8, no. 3 (June 29, 2024): 25. http://dx.doi.org/10.3390/epigenomes8030025.
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The heart is the first organ formed during mammalian development and functions to distribute nutrients and oxygen to other parts of the developing embryo. Cardiomyocytes are the major cell types of the heart and provide both structural support and contractile function to the heart. The successful differentiation of cardiomyocytes during early development is under tight regulation by physical and molecular factors. We have reviewed current studies on epigenetic factors critical for cardiomyocyte differentiation, including DNA methylation, histone modifications, chromatin remodelers, and noncoding RNAs. This review also provides comprehensive details on structural and morphological changes associated with the differentiation of fetal and postnatal cardiomyocytes and highlights their differences. A holistic understanding of all aspects of cardiomyocyte development is critical for the successful in vitro differentiation of cardiomyocytes for therapeutic purposes.
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Shimojo, Nobutake, Subrina Jesmin, Sohel Zaedi, Takeshi Otsuki, Seiji Maeda, Naoto Yamaguchi, Kazutaka Aonuma, Yuichi Hattori, and Takashi Miyauchi. "Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H474—H481. http://dx.doi.org/10.1152/ajpheart.00922.2006.
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Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effects of ET-1 on expression of VEGF and its receptors in cardiomyocytes are unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principal receptors, fetal liver kinase 1 and fms-like tyrosine kinase 1, in a concentration-dependent manner (10−12 to 10−6 M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area and [14C]leucine uptake by cardiomyocytes. Treatment with TA-0201 (10−6 M), an ETA-selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5–10 μg/ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ETA receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.
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Guo, Yuxuan, Yangpo Cao, Blake D. Jardin, Isha Sethi, Qing Ma, Behzad Moghadaszadeh, Emily C. Troiano, et al. "Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling." Proceedings of the National Academy of Sciences 118, no. 2 (December 23, 2020): e2008861118. http://dx.doi.org/10.1073/pnas.2008861118.
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The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.
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Edalat, Sam G., Yongjun Jang, Jongseong Kim, and Yongdoo Park. "Collagen Type I Containing Hybrid Hydrogel Enhances Cardiomyocyte Maturation in a 3D Cardiac Model." Polymers 11, no. 4 (April 16, 2019): 687. http://dx.doi.org/10.3390/polym11040687.
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In vitro maturation of cardiomyocytes in 3D is essential for the development of viable cardiac models for therapeutic and developmental studies. The method by which cardiomyocytes undergoes maturation has significant implications for understanding cardiomyocytes biology. The regulation of the extracellular matrix (ECM) by changing the composition and stiffness is quintessential for engineering a suitable environment for cardiomyocytes maturation. In this paper, we demonstrate that collagen type I, a component of the ECM, plays a crucial role in the maturation of cardiomyocytes. To this end, embryonic stem-cell derived cardiomyocytes were incorporated into Matrigel-based hydrogels with varying collagen type I concentrations of 0 mg, 3 mg, and 6 mg. Each hydrogel was analyzed by measuring the degree of stiffness, the expression levels of MLC2v, TBX18, and pre-miR-21, and the size of the hydrogels. It was shown that among the hydrogel variants, the Matrigel-based hydrogel with 3 mg of collagen type I facilitates cardiomyocyte maturation by increasing MLC2v expression. The treatment of transforming growth factor β1 (TGF-β1) or fibroblast growth factor 4 (FGF-4) on the hydrogels further enhanced the MLC2v expression and thereby cardiomyocyte maturation.
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Ying, Ying, Huazhang Zhu, Zhen Liang, Xiaosong Ma, and Shiwei Li. "GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway." Journal of Molecular Endocrinology 55, no. 3 (September 18, 2015): 245–62. http://dx.doi.org/10.1530/jme-15-0155.
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Activation of apoptosis in cardiomyocytes by saturated palmitic acids contributes to cardiac dysfunction in diabetic cardiomyopathy. Beta-catenin (b-catenin) is a transcriptional regulator of several genes involved in survival/anti-apoptosis. However, its role in palmitate-induced cardiomyocyte apoptosis remains unclear. Glucagon-like peptide 1 (GLP1) has been shown to exhibit potential cardioprotective properties. This study was designed to evaluate the role of b-catenin signalling in palmitate-induced cardiomyocyte apoptosis and the molecular mechanism underlying the protective effects of GLP1 on palmitate-stressed cardiomyocytes. Exposure of neonatal rat cardiomyocytes to palmitate increased the fatty acid transporter CD36-mediated intracellular lipid accumulation and cardiomyocyte apoptosis, decreased accumulation and nuclear translocation of active b-catenin, and reduced expression of b-catenin target protein survivin and BCL2. These detrimental effects of palmitate were significantly attenuated by GLP1 co-treatment. However, the anti-apoptotic effects of GLP1 were markedly abolished when b-catenin was silenced with a specific short hairpin RNA. Furthermore, analysis of the upstream molecules and mechanisms responsible for GLP1-associated cardiac protection revealed that GLP1 restored the decreased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3b (GSK3b) in palmitate-stimulated cardiomyocytes. In contrast, inhibition of Akt with an Akt-specific inhibitor MK2206 or blockade of GLP1 receptor (GLP1R) with a competitive antagonist exendin-(9–39) significantly abrogated the GLP1-mediated activation of GSK3b/b-catenin signalling, leading to increased apoptosis in palmitate-stressed cardiomyocytes. Collectively, our results demonstrated for the first time that the attenuated b-catenin signalling may contribute to palmitate-induced cardiomyocyte apoptosis, while GLP1 can protect cardiomyocytes from palmitate-induced apoptosis through activation of GLP1R/Akt/GSK3b-mediated b-catenin signalling.
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Wang, Li, Na Ning, Changtu Wang, Xiaohong Hou, Yuan Yuan, Yanan Ren, Cong Sun, Zi Yan, Xiaohui Wang, and Huirong Liu. "Endoplasmic reticulum stress contributed to β1-adrenoceptor autoantibody-induced reduction of autophagy in cardiomyocytes." Acta Biochimica et Biophysica Sinica 51, no. 10 (September 6, 2019): 1016–25. http://dx.doi.org/10.1093/abbs/gmz089.
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Abstract Autophagy reduction has been confirmed as an important mechanism in apoptosis induction. Our previous study showed that decreased autophagy induced by β1-adrenoceptor autoantibodies (β1-AAs) enhanced cardiomyocyte apoptosis and contributed to heart failure progression. Endoplasmic reticulum stress (ERS) is known to be an important mechanism in intracellular homeostasis and is closely related to autophagy. However, ERS in β1-AA-induced autophagy dysfunction of cardiomyocytes remains unclear. In this study, we used an active immunization rat model and H9c2 cardiomyocytes to study the role of ERS in β1-AA-induced autophagy. Results showed that prolonged action of β1-AAs significantly reduced the autophagy of myocardial tissues and H9c2 cardiomyocytes, and ERS and its related apoptotic pathways were significantly activated. Moreover, mRFP-GFP-LC3 double-labeled adenoviruses were used to detect cardiomyocyte autophagic flux to confirm that β1-AAs caused a significant decrease in autophagic flux in H9c2 cardiomyocytes. The ERS inhibitor, 4-phenylbutyrate (4-PBA), partially attenuated the β1-AA-induced reduction of cardiomyocyte autophagy, consistent with the effect of the mammalian target of rapamycin inhibitor rapamycin (Rapa). Compared to the pretreatment with 4-PBA or Rapa alone, pretreatment with the combination of 4-PBA and Rapa had a greater effect on attenuating the β1-AA-induced decrease in autophagy and β1-AA-induced apoptosis in cardiomyocytes. This study provides an experimental basis for the role of β1-AAs in the homeostatic maintenance of cardiomyocytes in patients with heart failure with respect to autophagy and ERS.
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Nakano, Stephanie J., John S. Walker, Lori A. Walker, Xiaotao Li, Yanmei Du, Shelley D. Miyamoto, Carmen C. Sucharov, et al. "Increased myocyte calcium sensitivity in end-stage pediatric dilated cardiomyopathy." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 6 (December 1, 2019): H1221—H1230. http://dx.doi.org/10.1152/ajpheart.00409.2019.
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Dilated cardiomyopathy (DCM) is the most common cause of heart failure (HF) in children, resulting in high mortality and need for heart transplantation. The pathophysiology underlying pediatric DCM is largely unclear; however, there is emerging evidence that molecular adaptations and response to conventional HF medications differ between children and adults. To gain insight into alterations leading to systolic dysfunction in pediatric DCM, we measured cardiomyocyte contractile properties and sarcomeric protein phosphorylation in explanted pediatric DCM myocardium ( N = 8 subjects) compared with nonfailing (NF) pediatric hearts ( N = 8 subjects). Force-pCa curves were generated from skinned cardiomyocytes in the presence and absence of protein kinase A. Sarcomeric protein phosphorylation was quantified with Pro-Q Diamond staining after gel electrophoresis. Pediatric DCM cardiomyocytes demonstrate increased calcium sensitivity (pCa50 =5.70 ± 0.0291), with an associated decrease in troponin (Tn)I phosphorylation compared with NF pediatric cardiomyocytes (pCa50 =5.59 ± 0.0271, P = 0.0073). Myosin binding protein C and TnT phosphorylation are also lower in pediatric DCM, whereas desmin phosphorylation is increased. Pediatric DCM cardiomyocytes generate peak tension comparable to that of NF pediatric cardiomyocytes [DCM 29.7 mN/mm2, interquartile range (IQR) 21.5–49.2 vs. NF 32.8 mN/mm2, IQR 21.5–49.2 mN/mm2; P = 0.6125]. In addition, cooperativity is decreased in pediatric DCM compared with pediatric NF (Hill coefficient: DCM 1.56, IQR 1.31–1.94 vs. NF 1.94, IQR 1.36–2.86; P = 0.0425). Alterations in sarcomeric phosphorylation and cardiomyocyte contractile properties may represent an impaired compensatory response, contributing to the detrimental DCM phenotype in children. NEW & NOTEWORTHY Our study is the first to demonstrate that cardiomyocytes from infants and young children with dilated cardiomyopathy (DCM) exhibit increased calcium sensitivity (likely mediated by decreased troponin I phosphorylation) compared with nonfailing pediatric cardiomyocytes. Compared with published values in adult cardiomyocytes, pediatric cardiomyocytes have notably decreased cooperativity, with a further reduction in the setting of DCM. Distinct adaptations in cardiomyocyte contractile properties may contribute to a differential response to pharmacological therapies in the pediatric DCM population.
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Auchampach, John, Lu Han, Guo N. Huang, Bernhard Kühn, John W. Lough, Caitlin C. O’Meara, Alexander Y. Payumo, et al. "Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration." American Journal of Physiology-Heart and Circulatory Physiology 322, no. 4 (April 1, 2022): H579—H596. http://dx.doi.org/10.1152/ajpheart.00666.2021.
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During the past two decades, the field of mammalian myocardial regeneration has grown dramatically, and with this expanded interest comes increasing claims of experimental manipulations that mediate bona fide proliferation of cardiomyocytes. Too often, however, insufficient evidence or improper controls are provided to support claims that cardiomyocytes have definitively proliferated, a process that should be strictly defined as the generation of two de novo functional cardiomyocytes from one original cardiomyocyte. Throughout the literature, one finds inconsistent levels of experimental rigor applied, and frequently the specific data supplied as evidence of cardiomyocyte proliferation simply indicate cell-cycle activation or DNA synthesis, which do not necessarily lead to the generation of new cardiomyocytes. In this review, we highlight potential problems and limitations faced when characterizing cardiomyocyte proliferation in the mammalian heart, and summarize tools and experimental standards, which should be used to support claims of proliferation-based remuscularization. In the end, definitive establishment of de novo cardiomyogenesis can be difficult to prove; therefore, rigorous experimental strategies should be used for such claims.
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Parameswaran, Sreejit, Sujeet Kumar, Rama Shanker Verma, and Rajendra K. Sharma. "Cardiomyocyte culture — an update on the in vitro cardiovascular model and future challenges." Canadian Journal of Physiology and Pharmacology 91, no. 12 (December 2013): 985–98. http://dx.doi.org/10.1139/cjpp-2013-0161.
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The success of any work with isolated cardiomyocytes depends on the reproducibility of cell isolation, because the cells do not divide. To date, there is no suitable in vitro model to study human adult cardiac cell biology. Although embryonic stem cells and induced pluripotent stem cells are able to differentiate into cardiomyocytes in vitro, the efficiency of this process is low. Isolation and expansion of human cardiomyocyte progenitor cells from cardiac surgical waste or, alternatively, from fetal heart tissue is another option. However, to overcome various issues related to human tissue usage, especially ethical concerns, researchers use large- and small-animal models to study cardiac pathophysiology. A simple model to study the changes at the cellular level is cultures of cardiomyocytes. Although primary murine cardiomyocyte cultures have their own advantages and drawbacks, alternative strategies have been developed in the last two decades to minimise animal usage and interspecies differences. This review discusses the use of freshly isolated murine cardiomyocytes and cardiomyocyte alternatives for use in cardiac disease models and other related studies.
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Li, Xiuju, Pratap Karki, Lei Lei, Huayan Wang, and Larry Fliegel. "Na+/H+ exchanger isoform 1 facilitates cardiomyocyte embryonic stem cell differentiation." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 1 (January 2009): H159—H170. http://dx.doi.org/10.1152/ajpheart.00375.2008.
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Embryonic stem cells provide one potential source of cardiomyocytes for cardiac transplantation; however, after differentiation of stem cells in vitro, cardiomyocytes usually account for only a minority of cells present. To gain insights into improving cardiomyocyte development from stem cells, we examined the role of the Na+/H+ exchanger isoform 1 (NHE1) in cardiomyocyte differentiation. NHE1 protein and message levels were induced by treatment of CGR8 cells to form embryoid bodies and cardiomyocytes. The NHE1 protein was present on the cell surface and NHE1 inhibitor-sensitive activity was detected. Inhibition of NHE1 activity during differentiation of CGR8 cells prevented cardiomyocyte differentiation as indicated by decreased message for transcription factors Nkx2-5 and Tbx5 and decreased levels of α-myosin heavy chain protein. Increased expression of NHE1 from an adenoviral vector facilitated cardiomyocyte differentiation. Similar results were found with cardiomyocyte differentiation of P19 embryonal carcinoma cells. CGR8 cells were treated to induce differentiation, but when differentiation was inhibited by dispersing the EBs, myocardial development was inhibited. The results demonstrate that NHE1 activity is important in facilitating stem cell differentiation to cardiomyocyte lineage. Elevated NHE1 expression appears to be triggered as part of the process that facilitates cardiomyocyte development.
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Chang, Wei-Han, Jing-Jing Yan, Xin Li, Hai-Yan Guo, and Yu Liu. "Original article. Effects of telmisartan on angiotensin II-induced cardiomyocyte hypertrophy and p-ERK1/2 phosphorylation in rat cultured cardiomyocytes." Asian Biomedicine 5, no. 4 (August 1, 2011): 459–65. http://dx.doi.org/10.5372/1905-7415.0504.060.
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Abstract Background: Cardiomyocyte hypertrophy is a common complication of hypertension, and is recognized as an important risk factor for cardiovascular diseases. Up to now, no study has been made on the effects of telmisartan on Ang II-induced cardiomyocyte hypertrophy. Objective: Investigate the effects of telmisartan on angiotensin II-induced cardiomyocyte hypertrophy and the phosphorylation of extracellular signal-regulated kinase (p-ERK1/2) in rat-cultured cardiomyocytes. Methods: Rat myocardial cells were cultured. Beating rates of the cardiomyocytes, cell volumes, total protein contents, protein synthesis rates, and ERK activity were measured. The phosphorylation of p-ERK1/2 was analyzed by Western blot. Results: Treatment of cultured cardiomyocytes with telmisartan inhibited angiotensin II-induced increases in cell volume, beating rate, total protein content and protein synthesis rate. Telmisartan markedly inhibited p-ERK1/2 phosphorylation in a dose- and time-dependent manner. Conclusion: Telmisartan could suppress cardiomyocyte hypertrophy induced by angiotensin II. The mechanism might be related to the inhibition of p-ERK1/2 phosphorylation.
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Jones, John L., Deborah Peana, Adam B. Veteto, Michelle D. Lambert, Zahra Nourian, Natalia G. Karasseva, Michael A. Hill, et al. "TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress." Cardiovascular Research 115, no. 1 (June 20, 2018): 46–56. http://dx.doi.org/10.1093/cvr/cvy156.
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Abstract Aims Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia–reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. Methods and results TRPV4 protein expression increased in cardiomyocytes of Aged (24–27 months) mice compared with Young (3–6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 μmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4−/−) mice. In Aged, pharmacological inhibition of TRPV4 (1 μmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Conclusions Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.
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Omatsu-Kanbe, Mariko, Ryo Fukunaga, Xinya Mi, and Hiroshi Matsuura. "Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes." Biomolecules 12, no. 7 (June 27, 2022): 896. http://dx.doi.org/10.3390/biom12070896.
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In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart.
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Engel, Felix B., Ludger Hauck, Manfred Boehm, Elizabeth G. Nabel, Rainer Dietz, and Rüdiger von Harsdorf. "p21CIP1 Controls Proliferating Cell Nuclear Antigen Level in Adult Cardiomyocytes." Molecular and Cellular Biology 23, no. 2 (January 15, 2003): 555–65. http://dx.doi.org/10.1128/mcb.23.2.555-565.2003.
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ABSTRACT Cell cycle withdrawal associated with terminal differentiation is responsible for the incapability of many organs to regenerate after injury. Here, we employed a cell-free system to analyze the molecular mechanisms underlying cell cycle arrest in cardiomyocytes. In this assay, incubation of S phase nuclei mixed with cytoplasmic extract of S phase cells and adult primary cardiomyocytes results in a dramatic reduction of proliferating cell nuclear antigen (PCNA) protein levels. This effect was blocked by the proteasome inhibitors MG132 and lactacystin, whereas actinomycin D and cycloheximide had no effect. Immunodepletion and addback experiments revealed that the effect of cardiomyocyte extract on PCNA protein levels is maintained by p21 but not p27. In serum-stimulated cardiomyocytes PCNA expression was reconstituted, whereas the protein level of p21 but not that of p27 was reduced. Cytoplasmic extract of serum-stimulated cardiomyocytes did not influence the PCNA protein level in S phase nuclei. Moreover, the hypertrophic effect of serum stimulation was blocked by ectopic expression of p21 and the PCNA protein level was found to be upregulated in adult cardiomyocytes derived from p21 knockout mice. Our data provide evidence that p21 regulates the PCNA protein level in adult cardiomyocytes, which has implications for cardiomyocyte growth control.
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Klug, M. G., M. H. Soonpaa, and L. J. Field. "DNA synthesis and multinucleation in embryonic stem cell-derived cardiomyocytes." American Journal of Physiology-Heart and Circulatory Physiology 269, no. 6 (December 1, 1995): H1913—H1921. http://dx.doi.org/10.1152/ajpheart.1995.269.6.h1913.
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The proliferative capacity of embryonic stem (ES) cell-derived cardiomyocytes was assessed. Enriched preparations of cardiomyocytes were isolated by microdissection of the cardiogenic regions of cultured embryoid bodies. The identity of the isolated cells was established by immunocytology, and mitotic activity was monitored by [3H]thymidine incorporation and pulse-chase experiments. ES-derived cardiomyocytes were mitotically active and predominantly mononucleated at 11 days after cardiogenic induction. By 21 days postinduction, cardiomyocyte DNA synthesis was markedly decreased, with a concomitant increase in the percentage of multinucleated cells. Interestingly, the duration of active cardiomyocyte reduplication in the ES system appeared to be roughly similar to that observed during normal murine cardiogenesis. Given these observations, as well as the genetic tractability of ES cells, ES-derived cardiogenesis might provide a useful in vitro system with which to assess the molecular regulation of the cardiomyocyte cell cycle.
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Kimura, Wataru, Yuji Nakada, and Hesham A. Sadek. "Hypoxia-induced myocardial regeneration." Journal of Applied Physiology 123, no. 6 (December 1, 2017): 1676–81. http://dx.doi.org/10.1152/japplphysiol.00328.2017.
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The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration.
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Seewald, Michael J., Peter Ellinghaus, Astrid Kassner, Ines Stork, Martina Barg, Sylvia Niebrügge, Stefan Golz, et al. "Genomic profiling of developing cardiomyocytes from recombinant murine embryonic stem cells reveals regulation of transcription factor clusters." Physiological Genomics 38, no. 1 (June 2009): 7–15. http://dx.doi.org/10.1152/physiolgenomics.90287.2008.
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Cardiomyocytes derived from pluripotent embryonic stem cells (ESC) have the advantage of providing a source for standardized cell cultures. However, little is known on the regulation of the genome during differentiation of ESC to cardiomyocytes. Here, we characterize the transcriptome of the mouse ESC line CM7/1 during differentiation into beating cardiomyocytes and compare the gene expression profiles with those from primary adult murine cardiomyocytes and left ventricular myocardium. We observe that the cardiac gene expression pattern of fully differentiated CM7/1-ESC is highly similar to adult primary cardiomyocytes and murine myocardium, respectively. This finding is underlined by demonstrating pharmacological effects of catecholamines and endothelin-1 on ESC-derived cardiomyocytes. Furthermore, we monitor the temporal changes in gene expression pattern during ESC differentiation with a special focus on transcription factors involved in cardiomyocyte differentiation. Thus, CM7/1-ESC-derived cardiomyocytes are a promising new tool for functional studies of cardiomyocytes in vitro and for the analysis of the transcription factor network regulating pluripotency and differentiation to cardiomyocytes.
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Segin, Sebastian, Michael Berlin, Christin Richter, Rebekka Medert, Veit Flockerzi, Paul Worley, Marc Freichel, and Juan E. Camacho Londoño. "Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling." Cells 9, no. 5 (April 28, 2020): 1092. http://dx.doi.org/10.3390/cells9051092.
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Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo. Cellular hypertrophy induced by angiotensin-II in embryonic cardiomyocytes from Orai1-deficient mice was blunted in comparison to cells from litter-matched control mice. Due to lethality of mice with ubiquitous Orai1 deficiency and to selectively analyze the role of Orai1 in adult cardiomyocytes, we generated a cardiomyocyte-specific and temporally inducible Orai1 knockout mouse line (Orai1CM–KO). Analysis of cardiac contractility by pressure-volume loops under basal conditions and of cardiac histology did not reveal differences between Orai1CM–KO mice and controls. Moreover, deletion of Orai1 in cardiomyocytes in adult mice did not protect them from angiotensin-II-induced cardiac remodeling, but cardiomyocyte cross-sectional area and cardiac fibrosis were enhanced. These alterations in the absence of Orai1 go along with blunted angiotensin-II-induced upregulation of the expression of Myoz2 and a lack of rise in angiotensin-II-induced STIM1 and Orai3 expression. In contrast to embryonic cardiomyocytes, where Orai1 contributes to the development of cellular hypertrophy, the results obtained from deletion of Orai1 in the adult myocardium reveal a protective function of Orai1 against the development of angiotensin-II-induced cardiac remodeling, possibly involving signaling via Orai3/STIM1-calcineurin-NFAT related pathways.
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Steinhelper, M. E., N. A. Lanson, K. P. Dresdner, J. B. Delcarpio, A. L. Wit, W. C. Claycomb, and L. J. Field. "Proliferation in vivo and in culture of differentiated adult atrial cardiomyocytes from transgenic mice." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 6 (December 1, 1990): H1826—H1834. http://dx.doi.org/10.1152/ajpheart.1990.259.6.h1826.
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Transgenic mice expressing atrial natriuretic factor-SV40 T-antigen fusion genes (ANF-TAG) developed unilateral right atrial tumors composed of differentiated dividing cardiomyocytes. The atrial tumors could be propagated as transplantable tumor lineages in syngeneic animals. Cardiomyocytes derived from ANF-TAG atrial tumors did not proliferate in tissue culture. However, cardiomyocytes derived from the transplantable tumor lines proliferated in culture, and these proliferating cardiomyocytes could be passaged in culture and recovered from frozen stocks. Cardiomyocytes from either tumor source were highly differentiated as determined by diverse functional and structural criteria. The cells continued to express numerous cardiac-specific proteins and retained ultrastructural features characteristic of cardiomyocytes including well-formed myofibrils, transverse tubules, and intercalated disks. In addition, the cultured cells displayed spontaneous electrical and contractile activities. These atrial tumor cardiomyocytes are a novel experimental resource for the identification of genes regulating the cardiomyocyte cell cycle.
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Potdar, Pravin D., and Preeti Prasannan. "Differentiation of Human Dermal Mesenchymal Stem Cells into Cardiomyocytes by Treatment with 5-Azacytidine: Concept for Regenerative Therapy in Myocardial Infarction." ISRN Stem Cells 2013 (March 28, 2013): 1–9. http://dx.doi.org/10.1155/2013/687282.
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Myocardial infarction (MI) is the leading cause of death worldwide. Stem cells regenerative medicine offers a promising approach to cure such degenerative disorders. Mesenchymal stem cells are thought to be one of the important types of stem cells which can differentiate into various lineages such as neuron, hepatocytes, and cardiomyocytes. In the present study, human dermal mesenchymal stem cells (hDMSCs) have been developed from human scalp punch biopsy and characterized for their mesenchymal phenotype so that these cells can be useful for differentiating into cardiomyocytes. 5-Azacytidine induces cardiomyocyte differentiation in vitro and therefore it has been used to differentiate hDMSCs cells into cardiomyocytes. It was observed that hDMSCs differentiated into cardiomyocyte within a period of 4 days to 15 days after treatment with 10 μM and 20 μM of 5-azacytidine. The cardiomyocyte phenotype was confirmed by studying expression of α-cardiac actin, β-myosin heavy chain, and cardiac troponin T. Thus, this paper describes the differentiation of hDMSCs into cardiomyocytes which can be further be used for treatment of MI. This type of cell-based cardiac therapy will offer a new hope for millions of patients worldwide who are suffering from heart disease.
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Haider, Husnain Kh, and Muhammad Ashraf. "Bone marrow stem cell transplantation for cardiac repair." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 6 (June 2005): H2557—H2567. http://dx.doi.org/10.1152/ajpheart.01215.2004.
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Cardiomyocytes respond to physiological or pathological stress only by hypertrophy and not by an increase in the number of functioning cardiomyocytes. However, recent evidence suggests that adult cardiomyocytes have the ability, albeit limited, to divide to compensate for the cardiomyocyte loss in the event of myocardial injury. Similarly, the presence of stem cells in the myocardium is a good omen. Their activation to participate in the repair process is, however, hindered by some as-yet-undetermined biological impediments. The rationale behind the use of adult stem cell transplantation is to supplement the inadequacies of the intrinsic repair mechanism of the heart and compensate for the cardiomyocyte loss in the event of injury. Various cell types including embryonic, fetal, and adult cardiomyocytes, smooth muscle cells, and stable cell lines have been used to augment the declining cardiomyocyte number and cardiac function. More recently, the focus has been shifted to the use of autologous skeletal myoblasts and bone marrow-derived stem cells. This review is a synopsis of some interesting aspects of the fast-emerging field of bone marrow-derived stem cell therapy for cardiac repair.
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Garbern, Jessica C., Qiang Li, Ren Liu, Estela Mancheno Juncosa, Zuwan Lin, Hannah L. Elwell, Junya Aoyama, Sokol K. Morgan, Jia Liu, and Richard T. Lee. "Abstract 10410: Human Stem Cell-Derived Endothelial Cells Suppress Automaticity of Stem Cell-Derived Cardiomyocytes." Circulation 144, Suppl_1 (November 16, 2021). http://dx.doi.org/10.1161/circ.144.suppl_1.10410.
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Clinical translation of stem cell therapies for heart disease is limited by a risk of potentially life-threatening ventricular arrhythmias seen following cardiomyocyte delivery in large animal models. Enhancing cardiomyocyte maturation may reduce this arrhythmogenic risk by reducing automaticity of delivered cardiomyocytes. We tested whether human induced pluripotent stem cell (hiPSC)-derived endothelial cells can enhance maturation and suppress automaticity of iPSC-derived cardiomyocytes in vitro. We found that co-culture of hiPSC-derived endothelial cells with hiPSC-derived cardiomyocytes significantly increased protein expression of cardiac troponin T, cardiac troponin I, Kir2.1, connexin 43, and CD36. In addition, using a stretchable mesh nanoelectronics device, we found that hiPSC-derived endothelial cells accelerated electrical maturation of hiPSC-derived cardiomyocytes and progressively suppressed cardiomyocyte automaticity in vitro (Figure). Using single cell RNA-seq, we identified a subpopulation of hiPSC-derived cardiomyocytes that is eliminated upon co-culture with hiPSC-derived endothelial cells. Further work will investigate whether this subpopulation of cardiomyocytes is responsible for automaticity of cardiomyocyte cultures. Figure. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes alone (CM only) or iPSC-derived cardiomyocytes co-cultured with iPSC-derived endothelial cells (CM+EC) were seeded onto a stretchable mesh nanoelectronics device. Unstimulated voltage tracings at day 30 of cardiomyocyte differentiation show cardiomyocytes with a slower beating rate and more narrow action potential when co-cultured with iPSC-derived endothelial cells compared to iPSC-derived cardiomyocytes alone.
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Liu, Xiuxiu, Wenjuan Pu, Lingjuan He, Yan Li, Huan Zhao, Yi Li, Kuo Liu, et al. "Cell proliferation fate mapping reveals regional cardiomyocyte cell-cycle activity in subendocardial muscle of left ventricle." Nature Communications 12, no. 1 (October 1, 2021). http://dx.doi.org/10.1038/s41467-021-25933-5.
Full textAbstract:
AbstractCardiac regeneration involves the generation of new cardiomyocytes from cycling cardiomyocytes. Understanding cell-cycle activity of pre-existing cardiomyocytes provides valuable information to heart repair and regeneration. However, the anatomical locations and in situ dynamics of cycling cardiomyocytes remain unclear. Here we develop a genetic approach for a temporally seamless recording of cardiomyocyte-specific cell-cycle activity in vivo. We find that the majority of cycling cardiomyocytes are positioned in the subendocardial muscle of the left ventricle, especially in the papillary muscles. Clonal analysis revealed that a subset of cycling cardiomyocytes have undergone cell division. Myocardial infarction and cardiac pressure overload induce regional patterns of cycling cardiomyocytes. Mechanistically, cardiomyocyte cell cycle activity requires the Hippo pathway effector YAP. These genetic fate-mapping studies advance our basic understanding of cardiomyocyte cell cycle activity and generation in cardiac homeostasis, repair, and regeneration.
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Suzuki, Shota, Shota Tanaka, Yusuke Kametani, Ayaka Umeda, Kosuke Nishinaka, Kaho Egawa, Yoshiaki Okada, Masanori Obana, and Yasushi Fujio. "Runx1 is upregulated by STAT3 and promotes proliferation of neonatal rat cardiomyocytes." Physiological Reports 11, no. 23 (December 2023). http://dx.doi.org/10.14814/phy2.15872.
Full textAbstract:
AbstractThough it is well known that mammalian cardiomyocytes exit cell cycle soon after birth, the mechanisms that regulate proliferation remain to be fully elucidated. Recent studies reported that cardiomyocytes undergo dedifferentiation before proliferation, indicating the importance of dedifferentiation in cardiomyocyte proliferation. Since Runx1 is expressed in dedifferentiated cardiomyocytes, Runx1 is widely used as a dedifferentiation marker of cardiomyocytes; however, little is known about the role of Runx1 in the proliferation of cardiomyocytes. The purpose of this study was to clarify the functional significance of Runx1 in cardiomyocyte proliferation. qRT‐PCR analysis and immunoblot analysis demonstrated that Runx1 expression was upregulated in neonatal rat cardiomyocytes when cultured in the presence of FBS. Similarly, STAT3 was activated in the presence of FBS. Interestingly, knockdown of STAT3 significantly decreased Runx1 expression, indicating Runx1 is regulated by STAT3. We next investigated the effect of Runx1 on proliferation. Immunofluorescence microscopic analysis using an anti‐Ki‐67 antibody revealed that knockdown of Runx1 decreased the ratio of proliferating cardiomyocytes. Conversely, Runx1 overexpression using adenovirus vector induced cardiomyocyte proliferation in the absence of FBS. Finally, RNA‐sequencing analysis revealed that Runx1 overexpression induced upregulation of cardiac fetal genes and downregulation of genes associated with fatty acid oxidation. Collectively, Runx1 is regulated by STAT3 and induces cardiomyocyte proliferation by juvenilizing cardiomyocytes.
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Shen, Junwei, Linlin Ma, Jing Hu, and Yanfei Li. "Single‐Cell Atlas of Neonatal Mouse Hearts Reveals an Unexpected Cardiomyocyte." Journal of the American Heart Association, November 28, 2023. http://dx.doi.org/10.1161/jaha.122.028287.
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Background Single‐cell RNA sequencing is widely used in cancer research and organ development because of its powerful ability to analyze cellular heterogeneity. However, its application in cardiomyocytes is dissatisfactory mainly because the cardiomyocytes are too large and fragile to withstand traditional single‐cell approaches. Methods and Results Through designing the isolation procedure of neonatal mouse cardiac cells, we provide detailed cellular atlases of the heart at single‐cell resolution across 4 different stages after birth. We have obtained 10 000 cardiomyocytes; to our knowledge, this is the most extensive reference framework to date. Moreover, we have discovered unexpected erythrocyte‐like cardiomyocyte–terminal cardiomyocytes, comprising more than a third of all cardiomyocytes. Only a few genes are highly expressed in these cardiomyocytes. They are highly differentiated cardiomyocytes that function as contraction pumps. In addition, we have identified 2 cardiomyocyte‐like conducting cells, lending support to the theory that the sinoatrial node pacemaker cells are specialized cardiomyocytes. Notably, we provide an initial blueprint for comprehensive interactions between cardiomyocytes and other cardiac cells. Conclusions This mouse cardiac cell atlas improves our understanding of cardiomyocyte heterogeneity and provides a valuable reference in response to varying physiological conditions and diseases.
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Farber, Gregory, Jiandong Liu, and Li Qian. "OSKM-mediated reversible reprogramming of cardiomyocytes regenerates injured myocardium." Cell Regeneration 11, no. 1 (January 17, 2022). http://dx.doi.org/10.1186/s13619-021-00106-3.
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AbstractCellular reprogramming has rapidly become a promising methodology to generate new cardiomyocytes from non-cardiomyocyte cell types. Using the transient expression of OSKM factors, Chen et al. demonstrate a unique reprogramming strategy involving the modulation of the resident adult cardiomyocyte identity to an immature proliferative state (Science 373:1537–40, 2021). This OSKM-mediated reversion results in the adoption by adult murine cardiomyocytes of a transcriptional profile similar to cardiomyocytes found in developing hearts, as well as increased proliferative capacity of these reprogrammed cardiomyocytes compared to mature cardiomyocytes. Furthermore, this novel approach enhances the regeneration of adult murine hearts post-myocardial injury. Although concerns and questions remain, the encouraging results of this study advance the field of cardiac regeneration by providing a new technique to generate cardiomyocytes as well as insights into cardiomyocyte dedifferentiation and its relation to proliferation.
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Yücel, Dogacan, Bayardo I. Garay, Rita C. R. Perlingeiro, and Jop H. van Berlo. "Stimulation of Cardiomyocyte Proliferation Is Dependent on Species and Level of Maturation." Frontiers in Cell and Developmental Biology 10 (May 19, 2022). http://dx.doi.org/10.3389/fcell.2022.806564.
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The heart is one of the least regenerative organs. This is in large part due to the inability of adult mammalian cardiomyocytes to proliferate and divide. In recent years, a number of small molecules and molecular targets have been identified to stimulate cardiomyocyte proliferation, including p38 inhibition, YAP-Tead activation, fibroblast growth factor 1 and Neuregulin 1. Despite these exciting initial findings, a therapeutic approach to enhance cardiomyocyte proliferation in vivo is still lacking. We hypothesized that a more comprehensive in vitro validation using live-cell imaging and assessment of the proliferative effects on various cardiomyocyte sources might identify the most potent proliferative stimuli. Here, we used previously published stimuli to determine their proliferative effect on cardiomyocytes from different species and isolated from different developmental timepoints. Although all stimuli enhanced DNA synthesis and Histone H3 phosphorylation in neonatal rat ventricular cardiomyocytes to similar degrees, these effects varied substantially in mouse cardiomyocytes and human iPSC-derived cardiomyocytes. Our results highlight p21 inhibition and Yap-Tead activation as potent proliferative strategies to induce cultured cardiomyocyte cell cycle activity across mouse, rat and human cardiomyocytes.
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Wang, Jie, William Morgan, Ankur Saini, Tao Liu, John Lough, and Lu Han. "Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells." Frontiers in Cell and Developmental Biology 10 (November 28, 2022). http://dx.doi.org/10.3389/fcell.2022.895162.
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Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult in vivo counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states. Two of those subpopulations were characterized by a mature, non-proliferative transcriptional profile. To further investigate the proliferation-maturation transition in cardiomyocytes, we induced loss-of-function of LMNB2, which represses cell cycle progression in primary cardiomyocytes in vivo. This resulted in increased maturation in LMNB2-inactivated cardiomyocytes, characterized by transcriptional profiles related to myofibril structure and energy metabolism. Furthermore, we identified maturation signatures and maturational trajectories unique for control and LMNB2-inactivated cardiomyocytes. By comparing these datasets with single-cell transcriptomes of human fetal hearts, we were able to define spatiotemporal maturation states in human iPSC-cardiomyocytes. Our results provide an integrated approach for comparing in vitro-differentiated cardiomyocytes with their in vivo counterparts and suggest a strategy to promote cardiomyocyte maturation.
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Chu, Dongyang, Thomas Rousselle, Courtney Cates, and Ji Li. "Abstract 170: Glucose Oxidation by Pyruvate Dehydrogenase Ameliorates Cradiomyocytes Contractility in Response to Hypoxic Stress." Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (May 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.170.
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Introduction: Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. Dichloroacetate (DCA), a PDH activator, has been revealed to increase glucose oxidation and reduce myocardial infarct size during ischemia and reperfusion. Hypothesis: Cardiac PDH activation plays a critical role in modulation of cardiomyocytes contractility and calcium signaling in response to hypoxia. Methods: Mechanical properties and intracellular Ca 2+ homeostasis were measured in isolated cardiomyocytes by IonOptix system. The stress signaling was evaluated using immunoblotting and immunoprecipitation analysis. Results: PDH activator DCA treatment significantly protects cardiomyocytes from hypoxia-induced contractile dysfunction as measured by maximal velocity of shortening (+dL/dt) and relengthening (–dL/dt), peak height and peak shortening (PS) amplitude, time-to-90% relengthening (TR90) in cardiomyocytes. However, DCA treatment did not show any protective effects on contractile functions of isolated cardiomyocytes from the cardiomyocyte specific PDH KO mouse hearts under hypoxic conditions. Intriguingly, the rise of intracellular Ca 2+ levels and intracellular ATP levels have no significant difference among wild type (WT) and PDH KO cardiomyocytes with and without DCA treatment. The results demonstrated that cardiomyocyte PDH KO does not affect cardiomyocyte contractility under normal physiological conditions, but significantly impaired the contractile functions of isolated cardiomyocytes under hypoxic conditions. Furthermore, the immunoblotting results showed that hypoxia triggered phosphorylation of AMP-activated protein kinase (AMPK) in isolated cardiomyocytes, but the AMPK phosphorylation was significantly impaired in PDH KO cardiomyocytes. DCA treatment clearly augmented ischemic AMPK phosphorylation in the isolated wild type (WT) but not in PDH KO cardiomyocytes. Conclusions: The glucose oxidation by pyruvate dehydrogenase (PDH) plays a critical role in cardiomyocyte contractility in response to hypoxic stress. PDH agonist DCA could be used for improve contractile function of cardiomyocytes under hypoxic insults.
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Ko, Toshiyuki, and Seitaro Nomura. "Manipulating Cardiomyocyte Plasticity for Heart Regeneration." Frontiers in Cell and Developmental Biology 10 (July 11, 2022). http://dx.doi.org/10.3389/fcell.2022.929256.
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Pathological heart injuries such as myocardial infarction induce adverse ventricular remodeling and progression to heart failure owing to widespread cardiomyocyte death. The adult mammalian heart is terminally differentiated unlike those of lower vertebrates. Therefore, the proliferative capacity of adult cardiomyocytes is limited and insufficient to restore an injured heart. Although current therapeutic approaches can delay progressive remodeling and heart failure, difficulties with the direct replenishment of lost cardiomyocytes results in a poor long-term prognosis for patients with heart failure. However, it has been revealed that cardiac function can be improved by regulating the cell cycle or changing the cell state of cardiomyocytes by delivering specific genes or small molecules. Therefore, manipulation of cardiomyocyte plasticity can be an effective treatment for heart disease. This review summarizes the recent studies that control heart regeneration by manipulating cardiomyocyte plasticity with various approaches including differentiating pluripotent stem cells into cardiomyocytes, reprogramming cardiac fibroblasts into cardiomyocytes, and reactivating the proliferation of cardiomyocytes.
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Lam, Nicholas T., Waleed M. Elhelaly, Ivan Menendez-Montes, Ching-Cheng Hsu, Ngoc Nguyen, Feng Xiao, Mahmoud S. Ahmed, et al. "Abstract 15792: Unchecked Cytokinesis Generates Highly Proliferative Mononuclear Cardiomyocytes at the Expense of Contractility." Circulation 146, Suppl_1 (November 8, 2022). http://dx.doi.org/10.1161/circ.146.suppl_1.15792.
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Introduction: A few days after birth in mouse cardiomyocytes, DNA synthesis occurs without cytokinesis leading to the majority of cardiomyocytes becoming binuclear instead of generating 2 daughter cells with one nucleus each. This results in cell cycle arrest of cardiomyocytes and the mouse heart is no longer able to regenerate. Hypothesis: A long-standing unanswered question in the field is whether multinucleation of cardiomyocytes is a result of cytokinesis failure. Methods and Results: To address this, we generated several transgenic mouse models to determine whether forced induction of cardiomyocyte cytokinesis generates mononuclear cardiomyocytes and restores the endogenous regenerative properties of the myocardium. We focused on two complementary regulators of cytokinesis, namely Polo-like kinase 1 (Plk1) and epithelial cell-transformation sequence 2 (Ect2), Here we report that cardiomyocyte-specific transgenic overexpression of constitutively active Plk1(T210D) alone promotes mitosis and cytokinesis in adult hearts, while overexpression of Ect2 alone promotes cytokinesis. Intriguingly, cardiomyocyte-specific overexpression of both Plk1(T210D) and Ect2 concomitantly (double transgenic) prevents binucleation of cardiomyocytes postnatally and results in widespread cardiomyocyte mitosis, cardiac enlargement, contractile failure and death before two weeks of age. Similarly, high-dose doxycycline inducible cardiomyocyte-specific overexpression of both proteins (inducible double transgenic) in the adult heart results in reversible widespread cardiomyocyte mitosis, cardiac enlargement, and contractile failure, while low-dose transient induction also results in significant cardiomyocyte proliferation and lower ejection fraction that is reversible after doxycycline is removed. Finally, we show that transient low-dose induction of both genes in adults improves left ventricular systolic function following myocardial infarction. Conclusion: Collectively, these results demonstrate that cytokinesis failure mediates cardiomyocyte multinucleation and cell cycle exit of postnatal cardiomyocytes but may be a protective mechanism to preserve the contractile function of the myocardium.
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Guo, Fang, Chen-Chen Zhang, Xi-Hui Yin, Ting Li, Cheng-Hu Fang, and Xi-Biao He. "Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition." Cell Death & Disease 11, no. 9 (September 2020). http://dx.doi.org/10.1038/s41419-020-03005-8.
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Abstract Heart is a multi-cellular organ made up of various cell types interacting with each other. Cardiomyocytes may benefit or suffer from crosstalk with noncardiomyocytes in response to diverse kinds of cardiac stresses. Proteasome dysfunction is a common cardiac stress which causes cardiac proteotoxicity and contributes to cardiac diseases such as heart failure and myocardial infarction. The role of crosstalk between cardiomyocytes and noncardiomyocytes in defense of cardiac proteotoxicity remains unknown. Here, we report a cardiomyocyte-specific survival upon proteasome inhibition in a heterogeneous culture consisting of cardiomyocytes and other three major cardiac cell types. Conversely, cardiomyocyte apoptosis is remarkably induced by proteasome inhibition in a homogeneous culture consisting of a majority of cardiomyocytes, demonstrating an indispensable role of noncardiomyocytes in the prevention of cardiomyocyte apoptosis resulting from proteasome inhibition. We further show that cardiomyocytes express brain natriuretic peptide (BNP) as an extracellular molecule in response to proteasome inhibition. Blockade of BNP receptor on noncardiomyocytes significantly exacerbated the cardiomyocyte apoptosis, indicating a paracrine function of cardiomyocyte-released extracellular BNP in activation of a protective feedback from noncardiomyocytes. Finally, we demonstrate that proteasome inhibition-activated transcriptional up-regulation of BNP in cardiomyocytes was associated with the dissociation of repressor element 1 silencing transcription factor (REST)/ histone deacetylase 1 (HDAC1) repressor complex from BNP gene promoter. Consistently, the induction of BNP could be further augmented by the treatment of HDAC inhibitors. We conclude that the crosstalk between cardiomyocytes and noncardiomyocytes plays a crucial role in the protection of cardiomyocytes from proteotoxicity stress, and identify cardiomyocyte-released BNP as a novel paracrine signaling molecule mediating this crosstalk. These findings provide new insights into the key regulators and cardioprotective mechanism in proteasome dysfunction-related cardiac diseases.
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Uosaki, Hideki, and Jun K. Yamashita. "Abstract P038: Cardiomyocyte Proliferating Chemicals: Activation of Proliferation of ESC/iPSC-Derived Cardiomyocytes." Circulation Research 109, suppl_1 (December 9, 2011). http://dx.doi.org/10.1161/res.109.suppl_1.ap038.
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Cardiomyocytes derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising cell sources for cardiac regeneration. Previously, we established a novel systematic cardiovascular cell induction system with mouse ESCs and iPSCs. ESC/iPSC-derived cardiomyocytes rarely proliferate after differentiation, similar to neonatal and adult cardiomyocytes. Cardiomyocyte proliferation is highly restricted and the regulating machineries of proliferation and growth arrest of cardiomyocytes are long-standing mysteries of cell biology. In order to establish cardiac regenerative medicine, it is critical to dissect and manipulate the machineries involved. Here we devised a novel approach using small molecules in an attempt to unravel the mystery and to manipulate ESC/iPSC-derived cardiomyocyte proliferation. We screened a chemical library containing well-established kinase inhibitors with high content screen to enhance mouse ESC-derived cardiomyocyte proliferation, and identified two novel chemical groups, extracellular signal-regulated kinase activators and Ca2+/calmodulin-dependent protein kinase II inhibitors, and two previously reported chemical groups, glycogen synthase kinase-3 inhibitors and a p38 mitogen-activated protein kinase inhibitior. Each chemical increased actual cardiomyocyte cell numbers two- to three-fold compared to control. An optimal combination of these chemicals strongly enhanced proliferation of ESC-derived cardiomyocytes and ESCM number was reached up to 14-fold. Expanded cells retained various functional and structural features of cardiomyocytes. These chemicals are robustly effective on cardiomyocytes from various sources including human iPSCs. Efficient combination of stem cell and chemical biology demonstrated a novel molecular mechanism of cardiomyocyte proliferation and offered a critical technological basis for cardiac regeneration.
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Sivankutty, Indu, Lucy Jung, August Y. Huang, Sarah Araten, Nazia Hilal, Christopher Walsh, Eunjung Alice Lee, Ming Hui Chen, and Sangita Choudhury. "Abstract P2063: Cellular Fusion Drives Polyploidization In Human Cardiomyocytes." Circulation Research 133, Suppl_1 (August 4, 2023). http://dx.doi.org/10.1161/res.133.suppl_1.p2063.
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Polyploidization is the roadblock to cardiac regeneration. Although endoreplication has been considered to be the main source of polyploidization in cardiomyocytes, recent evidence indicates transient cardiomyocyte fusion and its potential role in cardiac development in zebrafish. To understand polyploidization, it is essential to trace the lineage of cardiomyocytes. The existing lineage method is not suitable for studying the lineage in human heart cardiomyocytes. However, the accumulation of clonal somatic DNA mutation can be traced, and the clonal structure of these somatic mutations can be used for lineage reconstruction of human cardiomyocytes as these non-inherited clonal somatic mutations record the unique history of each somatic cell originating from a zygote and can be used as “endogenous barcodes.” Our analysis of ultra-deep targeted sequencing of ≈500 single cardiomyocyte nuclei using a panel of 253 validated clonal sSNVs revealed that 75.7% of the sequenced cardiomyocytes could be classified into one of the nine clades categorized based on the presence or absence of these mutations. Interestingly, we found that cardiomyocytes can have mutations from more than one clade, indicating the possibilities of cellular fusion in cardiomyocytes. Our results suggest that at least ~10% of tetraploid cardiomyocytes are generated from the fusion mechanism during development, whereas 60% higher ploidy cardiomyocytes are generated from the fusion. Further, we performed ATAC Seq and transcriptome analysis to find out the types of cells that are fused to generate polyploid cardiomyocytes in the human heart. Analysis of the transcriptome and chromatin peaks of tetraploid and higher ploidy cells unraveled a population of cells (cluster 7) that expressed chromatin peaks for endothelial markers (EGFL7) as well as cardiomyocyte-specific markers like TBX5, PLN, etc. Our study demonstrates cellular fusion in the adult human heart and the cell types involved in this fusion event. Understanding the generation of polyploid cardiomyocytes in the human heart might enable us to advance the mechanistic understanding of cardiomyocyte regeneration with the long-term goal of stimulating therapeutic cardiac regeneration.