Artykuły w czasopismach na temat „Pathological hypertrophy”
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Li, Wei-ming, Yi-fan Zhao, Guo-fu Zhu, Wen-hui Peng, Meng-yun Zhu, Xue-jing Yu, Wei Chen, Da-chun Xu i Ya-wei Xu. "Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload". Clinical Science 131, nr 2 (23.12.2016): 141–54. http://dx.doi.org/10.1042/cs20160664.
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Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.
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Yu, Qing, Wenxin Kou, Xu Xu, Shunping Zhou, Peipei Luan, Xiaopeng Xu, Hailing Li i in. "FNDC5/Irisin inhibits pathological cardiac hypertrophy". Clinical Science 133, nr 5 (1.03.2019): 611–27. http://dx.doi.org/10.1042/cs20190016.
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Abstract Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro. Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.
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Kang, Peter M., Patrick Yue, Zhilin Liu, Oleg Tarnavski, Natalya Bodyak i Seigo Izumo. "Alterations in apoptosis regulatory factors during hypertrophy and heart failure". American Journal of Physiology-Heart and Circulatory Physiology 287, nr 1 (lipiec 2004): H72—H80. http://dx.doi.org/10.1152/ajpheart.00556.2003.
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Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.
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Li, Peng-Long, Hui Liu, Guo-Peng Chen, Ling Li, Hong-Jie Shi, Hong-Yu Nie, Zhen Liu i in. "STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy". Hypertension 76, nr 4 (październik 2020): 1219–30. http://dx.doi.org/10.1161/hypertensionaha.120.14752.
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Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.
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JACOB, R., M. VOGT i H. RUPP. "Physiological and pathological hypertrophy*". Journal of Molecular and Cellular Cardiology 18 (1986): 35. http://dx.doi.org/10.1016/s0022-2828(86)80135-3.
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Tanaka, M., H. Fujiwara i C. Kawai. "Pathological features of hypertrophic cardiomyopathy without asymmetrical septal hypertrophy." Heart 56, nr 3 (1.09.1986): 294–97. http://dx.doi.org/10.1136/hrt.56.3.294.
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Hu, Chengyun, Feibiao Dai, Jiawu Wang, Lai Jiang, Di Wang, Jie Gao, Jun Huang i in. "Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice". Oxidative Medicine and Cellular Longevity 2022 (29.01.2022): 1–12. http://dx.doi.org/10.1155/2022/5067544.
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A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.
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Lu, Dan, Jizheng Wang, Jing Li, Feifei Guan, Xu Zhang, Wei Dong, Ning Liu, Shan Gao i Lianfeng Zhang. "Meox1 accelerates myocardial hypertrophic decompensation through Gata4". Cardiovascular Research 114, nr 2 (16.11.2017): 300–311. http://dx.doi.org/10.1093/cvr/cvx222.
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AbstractAimsPathological hypertrophy is the result of gene network regulation, which ultimately leads to adverse cardiac remodelling and heart failure (HF) and is accompanied by the reactivation of a ‘foetal gene programme’. The Mesenchyme homeobox 1 (Meox1) gene is one of the foetal programme genes. Meox1 may play a role in embryonic development, but its regulation of pathological hypertrophy is not known. Therefore, this study investigated the effect of Meox1 on pathological hypertrophy, including familial and pressure overload-induced hypertrophy, and its potential mechanism of action.Methods and resultsMeox1 expression was markedly down-regulated in the wild-type adult mouse heart with age, and expression was up-regulated in heart tissues from familial dilated cardiomyopathy (FDCM) mice of the cTnTR141W strain, familial hypertrophic cardiomyopathy (FHCM) mice of the cTnTR92Q strain, pressure overload-induced HF mice, and hypertrophic cardiomyopathy (HCM) patients. Echocardiography, histopathology, and hypertrophic molecular markers consistently demonstrated that Meox1 overexpression exacerbated the phenotypes in FHCM and in mice with thoracic aorta constriction (TAC), and that Meox1 knockdown improved the pathological changes. Gata4 was identified as a potential downstream target of Meox1 using digital gene expression (DGE) profiling, real-time PCR, and bioinformatics analysis. Promoter activity data and chromatin immunoprecipitation (ChIP) and Gata4 knockdown analyses indicated that Meox1 acted via activation of Gata4 transcription.ConclusionMeox1 accelerated decompensation via the downstream target Gata4, at least in part directly. Meox1 and other foetal programme genes form a highly interconnected network, which offers multiple therapeutic entry points to dampen the aberrant expression of foetal genes and pathological hypertrophy.
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Gao, Si, Xue-ping Liu, Li-hua Wei, Jing Lu i Peiqing Liu. "Upregulation of α-enolase protects cardiomyocytes from phenylephrine-induced hypertrophy". Canadian Journal of Physiology and Pharmacology 96, nr 4 (kwiecień 2018): 352–58. http://dx.doi.org/10.1139/cjpp-2017-0282.
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Cardiac hypertrophy often refers to the abnormal growth of heart muscle through a variety of factors. The mechanisms of cardiomyocyte hypertrophy have been extensively investigated using neonatal rat cardiomyocytes treated with phenylephrine. α-Enolase is a glycolytic enzyme with “multifunctional jobs” beyond its catalytic activity. Its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the change of α-enolase during cardiac hypertrophy and explore its role in this pathological process. We revealed that mRNA and protein levels of α-enolase were significantly upregulated in hypertrophic rat heart induced by abdominal aortic constriction and in phenylephrine-treated neonatal rat cardiomyocytes. Furthermore, knockdown of α-enolase by RNA interference in cardiomyocytes mimicked the hypertrophic responses and aggravated phenylephrine-induced hypertrophy without reducing the total glycolytic activity of enolase. In addition, knockdown of α-enolase led to an increase of GATA4 expression in the normal and phenylephrine-treated cardiomyocytes. Our results suggest that the elevation of α-enolase during cardiac hypertrophy is compensatory. It exerts a catalytic independent role in protecting cardiomyocytes against pathological hypertrophy.
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Luckey, Stephen W., Chris D. Haines, John P. Konhilas, Elizabeth D. Luczak, Antke Messmer-Kratzsch i Leslie A. Leinwand. "Cyclin D2 is a critical mediator of exercise-induced cardiac hypertrophy". Experimental Biology and Medicine 242, nr 18 (13.09.2017): 1820–30. http://dx.doi.org/10.1177/1535370217731503.
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A number of signaling pathways underlying pathological cardiac hypertrophy have been identified. However, few studies have probed the functional significance of these signaling pathways in the context of exercise or physiological pathways. Exercise studies were performed on females from six different genetic mouse models that have been shown to exhibit alterations in pathological cardiac adaptation and hypertrophy. These include mice expressing constitutively active glycogen synthase kinase-3β (GSK-3βS9A), an inhibitor of CaMK II (AC3-I), both GSK-3βS9A and AC3-I (GSK-3βS9A/AC3-I), constitutively active Akt (myrAkt), mice deficient in MAPK/ERK kinase kinase-1 (MEKK1−/−), and mice deficient in cyclin D2 (cyclin D2−/−). Voluntary wheel running performance was similar to NTG littermates for five of the mouse lines. Exercise induced significant cardiac growth in all mouse models except the cyclin D2−/− mice. Cardiac function was not impacted in the cyclin D2−/− mice and studies using a phospho-antibody array identified six proteins with increased phosphorylation (greater than 150%) and nine proteins with decreased phosphorylation (greater than 33% decrease) in the hearts of exercised cyclin D2−/− mice compared to exercised NTG littermate controls. Our results demonstrate that unlike the other hypertrophic signaling molecules tested here, cyclin D2 is an important regulator of both pathologic and physiological hypertrophy. Impact statement This research is relevant as the hypertrophic signaling pathways tested here have only been characterized for their role in pathological hypertrophy, and not in the context of exercise or physiological hypertrophy. By using the same transgenic mouse lines utilized in previous studies, our findings provide a novel and important understanding for the role of these signaling pathways in physiological hypertrophy. We found that alterations in the signaling pathways tested here had no impact on exercise performance. Exercise induced cardiac growth in all of the transgenic mice except for the mice deficient in cyclin D2. In the cyclin D2 null mice, cardiac function was not impacted even though the hypertrophic response was blunted and a number of signaling pathways are differentially regulated by exercise. These data provide the field with an understanding that cyclin D2 is a key mediator of physiological hypertrophy.
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Zeitz, Michael J., i James W. Smyth. "Translating Translation to Mechanisms of Cardiac Hypertrophy". Journal of Cardiovascular Development and Disease 7, nr 1 (10.03.2020): 9. http://dx.doi.org/10.3390/jcdd7010009.
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Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.
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Yuan, Yonggang, Wanzhong Peng, Yongxing Liu i Zesheng Xu. "Palmatine attenuates isoproterenol-induced pathological hypertrophy via selectively inhibiting HDAC2 in rats". International Journal of Immunopathology and Pharmacology 30, nr 4 (22.11.2017): 406–12. http://dx.doi.org/10.1177/0394632017742225.
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This study aimed to exploit the potential therapeutic value of palmatine in treatment of cardiac hypertrophy and the underlying molecular mechanism. Rat hypertrophy model was established by intraperitoneal isoproterenol (ISO) injection. The hypertrophy was evaluated with cardiac hypertrophic parameters, hemodynamic parameters, lipid profile, and non-specific cardiac markers. The animals were intraperitoneally administrated with either palmatine or vehicle. The relative expressions of ANP, BNP, HDAC2, HDAC5, KLF4, and INPP5F transcripts were determined by real-time polymerase chain reaction (PCR). The relative protein levels of HDAC2, HDAC5, KLF4, and INPP5F were analyzed by immunoblotting. Palmatine treatment significantly attenuated ISO-induced hypertrophy in rats and elicited remarkable repressions in ANP, BNP, and HDAC2 transcriptions but not HDAC5. The downstream effector genes KLF4 and INPP5F were greatly restored in a dose-dependent manner in response to palmatine treatment. Our data demonstrated that palmatine possessed promising therapeutic potential against hypertrophy, which was mediated by modulation of HDAC2-KLF4/INPP5F pathway.
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Joseph, Jacob, Lija Joseph, Nawal S. Shekhawat, Sulochana Devi, Junru Wang, Russell B. Melchert, Martin Hauer-Jensen i Richard H. Kennedy. "Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats". American Journal of Physiology-Heart and Circulatory Physiology 285, nr 2 (sierpień 2003): H679—H686. http://dx.doi.org/10.1152/ajpheart.00145.2003.
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A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.
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Zhou, Ning, Shaunrick Stoll i Hongyu Qiu. "VCP represses pathological cardiac hypertrophy". Aging 9, nr 12 (26.12.2017): 2469–70. http://dx.doi.org/10.18632/aging.101357.
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Shimizu, Ippei, i Tohru Minamino. "Physiological and pathological cardiac hypertrophy". Journal of Molecular and Cellular Cardiology 97 (sierpień 2016): 245–62. http://dx.doi.org/10.1016/j.yjmcc.2016.06.001.
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Kavazis, Andreas N. "Pathological vs. physiological cardiac hypertrophy". Journal of Physiology 593, nr 17 (1.09.2015): 3767. http://dx.doi.org/10.1113/jp271161.
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Harrison, Brooke C., Charles R. Roberts, David B. Hood, Meghan Sweeney, Jody M. Gould, Erik W. Bush i Timothy A. McKinsey. "The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression". Molecular and Cellular Biology 24, nr 24 (15.12.2004): 10636–49. http://dx.doi.org/10.1128/mcb.24.24.10636-10649.2004.
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ABSTRACT Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.
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Liao, Hai-han, Nan Zhang, Yan-yan Meng, Hong Feng, Jing-jing Yang, Wen-jin Li, Si Chen, Hai-ming Wu, Wei Deng i Qi-zhu Tang. "Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway". Oxidative Medicine and Cellular Longevity 2019 (6.12.2019): 1–14. http://dx.doi.org/10.1155/2019/6304058.
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Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.
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Yang, Jin, Xuhui Feng, Qiong Zhou, Wei Cheng, Ching Shang, Pei Han, Chiou-Hong Lin, Huei-Sheng Vincent Chen, Thomas Quertermous i Ching-Pin Chang. "Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex". Proceedings of the National Academy of Sciences 113, nr 38 (6.09.2016): E5628—E5635. http://dx.doi.org/10.1073/pnas.1525078113.
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Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.
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Brown, R. Dale, S. Kelly Ambler, Min Li, Timothy M. Sullivan, Lauren N. Henry, Joseph T. Crossno, Carlin S. Long, Timothy P. Garrington i Kurt R. Stenmark. "MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension". American Journal of Physiology-Heart and Circulatory Physiology 304, nr 2 (15.01.2013): H269—H281. http://dx.doi.org/10.1152/ajpheart.00158.2012.
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Pulmonary hypertension (PH) results in pressure overload of the right ventricle (RV) of the heart, initiating pathological RV remodeling and ultimately leading to right heart failure. Substantial research indicates that signaling through the MAPK superfamily mediates pathological cardiac remodeling. These considerations led us to test the hypothesis that the regulatory protein MAPKKK-2 (MEKK2) contributes to RV hypertrophy in hypoxia-induced PH. Transgenic mice with global knockout of MEKK2 (MEKK2−/− mice) and age-matched wild-type (WT) mice were exposed to chronic hypobaric hypoxia (10% O2, 6 wk) and compared with animals under normoxia. Exposure to chronic hypoxia induced PH in WT and MEKK2−/− mice. In response to PH, WT mice showed RV hypertrophy, demonstrated as increased ratio of RV weight to body weight, increased RV wall thickness at diastole, and increased cardiac myocyte size compared with normoxic control animals. In contrast, each of these measures of RV hypertrophy seen in WT mice after chronic hypoxia was attenuated in MEKK2−/− mice. Furthermore, chronic hypoxia elicited altered programs of hypertrophic and inflammatory gene expression consistent with pathological RV remodeling in WT mice; MEKK2 deletion selectively inhibited inflammatory gene expression compared with WT mice. The actions of MEKK2 were mediated in part through regulation of the abundance and phosphorylation of its effector, ERK5. In conclusion, signaling by MEKK2 contributes to RV hypertrophy and altered myocardial inflammatory gene expression in response to hypoxia-induced PH. Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathological remodeling in human PH.
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Buss, Sebastian J., Johannes H. Riffel, Pratima Malekar, Marco Hagenmueller, Christina Asel, Min Zhang, Celine Weiss, Hugo A. Katus i Stefan E. Hardt. "Chronic Akt blockade aggravates pathological hypertrophy and inhibits physiological hypertrophy". American Journal of Physiology-Heart and Circulatory Physiology 302, nr 2 (styczeń 2012): H420—H430. http://dx.doi.org/10.1152/ajpheart.00211.2011.
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The attenuation of adverse myocardial remodeling and pathological left ventricular (LV) hypertrophy is one of the hallmarks for improving the prognosis after myocardial infarction (MI). The protein kinase Akt plays a central role in regulating cardiac hypertrophy, but the in vivo effects of chronic pharmacological inhibition of Akt are unknown. We investigated the effect of chronic Akt blockade with deguelin on the development of pathological [MI and aortic banding (AB)] and physiological (controlled treadmill running) hypertrophy. Primary cardiomyocyte cultures were incubated with 10 μmol deguelin for 48 h, and Wistar rats were treated orally with deguelin (4.0 mg·kg−1·day−1) for 4 wk starting 1 day after the induction of MI or AB. Exercise-trained animals received deguelin for 4 wk during the training period. In vitro, we observed reduced phosphorylation of Akt and glycogen synthase kinase (GSK)-3β after an incubation with deguelin, whereas MAPK signaling was not significantly affected. In vivo, treatment with deguelin led to attenuated phosphorylation of Akt and GSK-3β 4 wk after MI. These animals showed significantly increased heart weights and impaired LV function with increased end-diastolic diameters (12.0 ± 0.3 vs. 11.1 ± 0.3 mm, P < 0.05), end-diastolic volumes (439 ± 8 vs. 388 ± 18 μl, P < 0.05), and cardiomyocyte sizes (+20%, P < 0.05) compared with MI animals receiving vehicle treatment. Furthermore, activation of Ca2+/calmodulin-dependent kinase II in deguelin-treated MI animals was increased compared with the vehicle-treated group. Four wk after AB, we observed an augmentation of pathological hypertrophy in the deguelin-treated group with a significant increase in heart weights and cardiomyocyte sizes (>20%, P < 0.05). In contrast, the development of physiological hypertrophy was inhibited by deguelin treatment in exercise-trained animals. In conclusion, chronic Akt blockade with deguelin aggravates adverse myocardial remodeling and antagonizes physiological hypertrophy.
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Deng, Yawen, Zhitong Li, Xiangbo An, Rui Fan, Yao Wang, Jiatian Li, Xiaolei Yang, Jiawei Liao i Yunlong Xia. "Hyperhomocysteinemia Promotes Cardiac Hypertrophy in Hypertension". Oxidative Medicine and Cellular Longevity 2022 (22.08.2022): 1–16. http://dx.doi.org/10.1155/2022/1486157.
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Hyperhomocysteinemia (HHcy) is positively linked with several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac hypertrophy are still unclear. Here, we focused on the effects and underlying mechanisms of HHcy in hypertensive cardiac hypertrophy, one of the most common and typical types of pathological cardiac hypertrophy. By a retrospective analysis of the association between HHcy and cardiac hypertrophy in a hypertensive cohort, we found that the prevalence of HHcy was higher in patients with hypertrophy and significantly associated with the presence of cardiac hypertrophy after adjusting for other conventional risk factors. In mice, HHcy induced by a methionine (2% wt/wt) diet feeding significantly promoted cardiac hypertrophy as well as cardiac inflammation and fibrosis induced by 3-week angiotensin ІІ (AngІІ) infusion (1000 ng/kg/min), while folic acid (0.006% wt/wt) supplement corrected HHcy and attenuated AngII-stimulated cardiac phenotypes. Mechanistic studies further showed that homocysteine (Hcy) exacerbated AngII-stimulated expression of Calcineurin and nuclear factor of activated T cells (NFAT), which could be attenuated by folic acid both in mice and in neonatal rat cardiomyocytes. Moreover, treatment with cyclosporin A, an inhibitor of Calcineurin, blocked Hcy-stimulated Calcineurin-NFAT signaling and hypertrophy in neonatal rat cardiomyocytes. In conclusion, our study indicates that HHcy promotes cardiac hypertrophy in hypertension, and Calcineurin-NFAT pathway might be involved in the pro-hypertrophic effect of Hcy.
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Kong, Sek Won, Natalya Bodyak, Patrick Yue, Zhilin Liu, Jeffrey Brown, Seigo Izumo i Peter M. Kang. "Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats". Physiological Genomics 21, nr 1 (21.03.2005): 34–42. http://dx.doi.org/10.1152/physiolgenomics.00226.2004.
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Cardiac hypertrophy is a complex and nonhomogenous response to various stimuli. In this study, we used high-density oligonucleotide microarray to examine gene expression profiles during physiological hypertrophy, pathological hypertrophy, and heart failure in Dahl salt-sensitive rats. There were changes in 404/3,160 and 874/3,160 genes between physiological and pathological hypertrophy and the transition from hypertrophy to heart failure, respectively. There were increases in stress response genes (e.g., heat shock proteins) and inflammation-related genes (e.g., pancreatitis-associated protein and arachidonate 12-lipoxygenase) in pathological processes but not in physiological hypertrophy. Furthermore, atrial natriuretic factor and brain natriuretic protein showed distinctive changes that are very specific to different conditions. In addition, we used a resampling-based gene score-calculating method to define significantly altered gene clusters, based on Gene Ontology classification. It revealed significant alterations in genes involved in the apoptosis pathway during pathological hypertrophy, suggesting that the apoptosis pathway may play a role during the transition to heart failure. In addition, there were significant changes in glucose/insulin signaling, protein biosynthesis, and epidermal growth factor signaling during physiological hypertrophy but not during pathological hypertrophy.
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Ago, Tetsuro, i Junichi Sadoshima. "From Contractile Enhancement to Pathological Hypertrophy". Journal of the American College of Cardiology 66, nr 3 (lipiec 2015): 273–77. http://dx.doi.org/10.1016/j.jacc.2015.05.058.
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Wehbe, Nadine, Suzanne Nasser, Gianfranco Pintus, Adnan Badran, Ali Eid i Elias Baydoun. "MicroRNAs in Cardiac Hypertrophy". International Journal of Molecular Sciences 20, nr 19 (23.09.2019): 4714. http://dx.doi.org/10.3390/ijms20194714.
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Like other organs, the heart undergoes normal adaptive remodeling, such as cardiac hypertrophy, with age. This remodeling, however, is intensified under stress and pathological conditions. Cardiac remodeling could be beneficial for a short period of time, to maintain a normal cardiac output in times of need; however, chronic cardiac hypertrophy may lead to heart failure and death. MicroRNAs (miRNAs) are known to have a role in the regulation of cardiac hypertrophy. This paper reviews recent advances in the field of miRNAs and cardiac hypertrophy, highlighting the latest findings for targeted genes and involved signaling pathways. By targeting pro-hypertrophic genes and signaling pathways, some of these miRNAs alleviate cardiac hypertrophy, while others enhance it. Therefore, miRNAs represent very promising potential pharmacotherapeutic targets for the management and treatment of cardiac hypertrophy.
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Xie, Xin, Hai-Lian Bi, Song Lai, Yun-Long Zhang, Nan Li, Hua-Jun Cao, Ling Han, Hong-Xia Wang i Hui-Hua Li. "The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation". Science Advances 5, nr 5 (maj 2019): eaau0495. http://dx.doi.org/10.1126/sciadv.aau0495.
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Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.
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Watson, Peter A., Jane E. B. Reusch, Sylvia A. McCune, Leslie A. Leinwand, Stephen W. Luckey, John P. Konhilas, David A. Brown i in. "Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise". American Journal of Physiology-Heart and Circulatory Physiology 293, nr 1 (lipiec 2007): H246—H259. http://dx.doi.org/10.1152/ajpheart.00734.2006.
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Potential regulation of two factors linked to physiological outcomes with left ventricular (LV) hypertrophy, resistance to apoptosis, and matching of metabolic capacity, by the transcription factor cyclic-nucleotide regulatory element binding protein (CREB), was examined in the two models of physiological LV hypertrophy: involuntary treadmill running of female Sprague-Dawley rats and voluntary exercise wheel running in female C57Bl/6 mice. Comparative studies were performed in the models of pathological LV hypertrophy and failure: the spontaneously hypertension heart failure (SHHF) rat and the hypertrophic cardiomyopathy (HCM) transgenic mouse, a model of familial idiopathic cardiomyopathy. Activating CREB serine-133 phosphorylation was decreased early in remodeling in response to both physiological (decreased 50–80%) and pathological (decreased 60–80%) hypertrophic stimuli. Restoration of LV CREB phosphorylation occurred concurrent with completion of physiological hypertrophy (94% of sedentary control), but remained decreased (by 90%) during pathological hypertrophy. In all models of hypertrophy, CREB phosphorylation/activation demonstrated strong positive correlations with 1) expression of the anti-apoptotic protein bcl-2 (a CREB-dependent gene) and subsequent reductions in the activation of caspase 9 and caspase 3; 2) expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1; a major regulator of mitochondrial content and respiratory capacity), and 3) LV mitochondrial respiratory rates and mitochondrial protein content. Exercise-induced increases in LV mitochondrial respiratory capacity were commensurate with increases observed in LV mass, as previously reported in the literature. Exercise training of SHHF rats and HCM mice in LV failure improved cardiac phenotype, increased CREB activation (31 and 118%, respectively), increased bcl-2 content, improved apoptotic status, and enhanced PGC-1 content and mitochondrial gene expression. Adenovirus-mediated expression of constitutively active CREB in neonatal rat cardiac recapitulated exercise-induced upregulation of PGC-1 content and mitochondrial oxidative gene expression. These data support a model wherein CREB contributes to physiological hypertrophy by enhancing expression of genes important for efficient oxidative capacity and resistance to apoptosis.
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Oldfield, Christopher J., Todd A. Duhamel i Naranjan S. Dhalla. "Mechanisms for the transition from physiological to pathological cardiac hypertrophy". Canadian Journal of Physiology and Pharmacology 98, nr 2 (luty 2020): 74–84. http://dx.doi.org/10.1139/cjpp-2019-0566.
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The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca2+-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.
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Ţarcă, Elena, Elena Cojocaru, Alina Costina Luca, Laura Mihaela Trandafir, Solange Tamara Roşu, Valentin Munteanu, Viorel Țarcă, Cristian Constantin Budacu i Claudia Florida Costea. "Unusual Case of Masseter Muscle Hypertrophy in Adolescence—Case Report and Literature Overview". Diagnostics 12, nr 2 (16.02.2022): 505. http://dx.doi.org/10.3390/diagnostics12020505.
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Unilateral hypertrophy of the masseter muscle is a very rare pathological entity in children. Its etiology is uncertain and it requires a high degree of suspicion, as it must be differentiated from other conditions of the masseter area. As there are few pathological studies to elucidate this condition, we report a rare case of unilateral masseter muscle hypertrophy in a 16-year-old female patient with gradual onset of a painless swelling in the posterior left cheek which caused facial asymmetry with repercussions on the patient’s self-image. The diagnosis of unilateral masseter muscle hypertrophy was suggested by clinical examination, ultrasound scanning, and nuclear magnetic resonance, and was confirmed by histologic examination two years later when the patient returned for the surgical correction. The pathological findings report showed fragments of skeletal muscle with hypertrophic fibers associated with normal-sized muscle fibers in both longitudinal and transverse sections. The postoperative evaluation was favorable as both the adolescent and her family were satisfied with her look on the 14th day, 1st year, and 3rd year follow-ups. In conclusion, unilateral masseter muscle hypertrophy in adolescence is a sensitive problem due to the psychological implications of facial appearance. Definite diagnosis and treatment of the hypertrophied muscle is the ideal solution.
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Haines, Christopher D., Pamela A. Harvey i Leslie A. Leinwand. "Estrogens Mediate Cardiac Hypertrophy in a Stimulus-Dependent Manner". Endocrinology 153, nr 9 (1.09.2012): 4480–90. http://dx.doi.org/10.1210/en.2012-1353.
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The incidence of cardiac hypertrophy, an established risk factor for heart failure, is generally lower in women compared with men, but this advantage is lost after menopause. Although it is widely believed that estrogens are cardioprotective, there are contradictory reports, including increased cardiac events in postmenopausal women receiving estrogens and enhanced cardiac protection from ischemic injury in female mice without estrogens. We exposed aromatase knockout (ArKO) mice, which produce no estrogens, to both pathologic and physiologic stimuli. This model allows an investigation into the effects of a complete, chronic lack of estrogens in male and female hearts. At baseline, female ArKO mice had normal-sized hearts but decreased cardiac function and paradoxically increased phosphorylation of many progrowth kinases. When challenged with the pathological stimulus, isoproterenol, ArKO females developed 2-fold more hypertrophy than wild-type females. In contrast, exercise-induced physiological hypertrophy was unaffected by the absence of estrogens in either sex, although running performance was blunted in ArKO females. Thus, loss of estrogen signaling in females, but not males, impairs cardiac function and sensitizes the heart to pathological insults through up-regulation of multiple hypertrophic pathways. These findings provide insight into the apparent loss of cardioprotection after menopause and suggest that caution is warranted in the long-term use of aromatase inhibitors in the setting of breast cancer prevention.
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Qian, Yanxia, Mingming Zhang, Ningtian Zhou, Xiaohan Xu, Jiahui Zhang, Qiang Ding i Junhong Wang. "A long noncoding RNA CHAIR protects the heart from pathological stress". Clinical Science 134, nr 13 (lipiec 2020): 1843–57. http://dx.doi.org/10.1042/cs20200149.
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Abstract Mammalian genomes have been found to be extensively transcribed. In addition to classic protein coding genes, a large numbers of long noncoding genes (lncRNAs) have been identified, while their functions, especially in heart diseases, remain to be established. We hypothesized that heart failure progression is controlled by tissue-specific lncRNAs. In the present study, we found that the cardiac-enriched lncRNA 4632428C04Rik, named as cardiomyocyte hypertrophic associated inhibitory RNA (CHAIR), is dynamically regulated during heart development, is expressed at low levels in embryonic hearts and accumulated at high levels in adult hearts. More interestingly, the lncRNA was down-regulated during cardiac hypertrophy and failure both in mice and humans. Importantly, loss of lncRNA CHAIR has no effects on normal hearts, whereas it results in accelerated heart function decline, increased hypertrophy, and exacerbated heart failure in response to stress. In contrast, restoring the expression of lncRNA CHAIR rescued the hearts from hypertrophy and failure. DNMT3A was recruited to CHAIR promoter during heart failure to suppress its expression. Reciprocally, CHAIR interacted with DNMT3A to inhibit its DNA-binding activity. Taken together, our data revealed a new cardioprotective lncRNA that represses heart failure through an epigenetic mechanism.
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Chen, Lijuan, Jia Huang, Yanxiao Ji, Xiaojing Zhang, Pixiao Wang, Keqiong Deng, Xi Jiang, Genshan Ma i Hongliang Li. "Tripartite motif 32 prevents pathological cardiac hypertrophy". Clinical Science 130, nr 10 (1.04.2016): 813–28. http://dx.doi.org/10.1042/cs20150619.
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This study presents the first evidence that TRIM32 protects against pathological cardiac hypertrophy by suppressing Akt-dependent signalling pathways. Therefore TRIM32 might be a potential therapeutic strategy for the prevention and treatment of cardiac hypertrophy and heart failure.
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Abibillaev, Damirbek, i Fuat Kocyigit. "Athletic heart adaptation, pathological hypertrophy and sudden cardiac death". Heart, Vessels and Transplantation 4, Issue 2 (27.05.2020): 55. http://dx.doi.org/10.24969/hvt.2020.199.
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Cardiac hypertrophy has been continuing as the subject of the ‘hottest’ topic in research field for a long time since it creates pathophysiologic and clinical issues by structural and functional alterations of heart. Probably, it is explained by the prevalence of cardiovascular disorders in all-cause mortality. It seems that, on the basis of a contemporary data, the perception of ‘benign’ nature of the cardiac hypertrophy in athletic population is blurred. The improvement of imaging modalities and assessment tools largely contributed to comprehensive integration of scientific and clinical standpoints of athletic hypertrophy. Conventionally pathologic hypertrophy believed to be developed in a case of cardiovascular diseases, while the athlete’s heart resulted by long-standing physical training. According to recent evidence, a gray zone of hypertrophy became emerged between physiological and pathological entities, which require further extensive investigations. The emerging huge challenges in sports cardiology are overtraining and doping abuse of elite athletes by the development of an excessive cardiac hypertrophy with the increased risk of cardiovascular adverse outcomes. Additionally, the higher prevalence of sudden cardiac death in sportsmen compared to sedentary matches, especially in case of athletes with known or suspected cardiovascular diseases necessitated scrupulous investigation of athletic heart syndrome. The development, variety and severity of cardiac hypertrophy fluctuate by sportive branch and training mode. The significance of problem is more emphasized when cohort studies represented survival differences by means of cardiovascular parameters between athletes and sedentary subjects and cardiac patients. In this review, we aimed to represent recent physiological and clinical standpoints regarding to athletic heart syndrome as well as its difference from sedentary heart changes and pathological hypertrophy, its association with sudden cardiac death.
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Grund, Andrea, Malgorzata Szaroszyk, Janina K. Döppner, Mona Malek Mohammadi, Badder Kattih, Mortimer Korf-Klingebiel, Anna Gigina i in. "A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload". Cardiovascular Research 115, nr 1 (20.06.2018): 71–82. http://dx.doi.org/10.1093/cvr/cvy154.
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Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.
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Su, Dongmei, Sun Jing, Lina Guan, Qian Li, Huiling Zhang, Xiaobo Gao i Xu Ma. "Role of Nodal–PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy". Biochemistry and Cell Biology 92, nr 3 (czerwiec 2014): 183–90. http://dx.doi.org/10.1139/bcb-2013-0124.
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Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal–PITX2C pathway on HG-induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms.
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Bi, Hai-Lian, Xiao-Li Zhang, Yun-Long Zhang, Xin Xie, Yun-Long Xia, Jie Du i Hui-Hua Li. "The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor". Science Advances 6, nr 16 (kwiecień 2020): eaax4826. http://dx.doi.org/10.1126/sciadv.aax4826.
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Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1–treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.
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Iemitsu, Motoyuki, Takashi Miyauchi, Seiji Maeda, Satoshi Sakai, Tsutomu Kobayashi, Nobuharu Fujii, Hitoshi Miyazaki, Mitsuo Matsuda i Iwao Yamaguchi. "Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, nr 6 (1.12.2001): R2029—R2036. http://dx.doi.org/10.1152/ajpregu.2001.281.6.r2029.
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Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of β1-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of β1-adrenergic receptor kinase mRNA, which inhibits β1-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.
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Grieco, Teresa, Vito Gomes, Alfredo Rossi, Carmen Cantisani, Maria Elisabetta Greco, Giovanni Rossi, Alvise Sernicola i Giovanni Pellacani. "The Pathological Culprit of Neuropathic Skin Pain in Long COVID-19 Patients: A Case Series". Journal of Clinical Medicine 11, nr 15 (31.07.2022): 4474. http://dx.doi.org/10.3390/jcm11154474.
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Cutaneous neurosensory symptoms have become increasingly reported findings in COVID-19; however, these virus-related manifestations are largely overlooked, and their pathology is poorly understood. Moreover, alterations of skin sensibility currently recognize no clear histopathology substrate. The purpose of this study was to provide pathology evidence of neurosensory skin system involvement in COVID-19 patients complaining of subjective neurological symptoms affecting the skin. Out of 142 patients, six long COVID-19 cases complaining of cutaneous subjective neurological symptoms assessed on an NTSS-6 questionnaire underwent histopathological and immunohistochemical analyses of skin areas affected by paroxysmal diffuse burning and itching sensations. Two patients also performed electroneurography examination. The histology investigation showed hypertrophic glomus vascular bodies with hypertrophic S100+ perineural sheath cells and adjacent hypertrophy of the nerve branches associated with increased basophil polysaccharide matrix. Electroneurography revealed disturbances of A-delta and C dermal neuronal fibers. The main limitation of this study consisted of a limited number of skin biopsy samples, requiring further investigation. Histopathology findings are consistent with hypertrophy of nerve endings, suggesting a condition such as “dermal hyperneury”, a recently reported small nerve hypertrophy condition affecting sensory C fibers. Such a neuropathic basis could explain dysesthesia experienced by the patients, as previously described in postherpetic neuralgia.
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Nosenko, N. M., D. V. Shchehlov, M. Yu Mamonova i Ya E. Kudelskyi. "Left ventricular hypertrophy: differential diagnosis". Endovascular Neuroradiology 30, nr 4 (11.03.2020): 49–58. http://dx.doi.org/10.26683/2304-9359-2019-4(30)-49-58.
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There are some imaging methods for the diagnosis of left ventricular hypertrophy. Such as echocardiography, computed tomography, magnetic resonance imaging. These methods help to identify changes at different stages, evaluate the prognosis, stratify the risk and differential diagnosis.The left ventricle hypertrophy is a condition that may be due to physiological adaptation due to overload. For example, in patients with arterial hypertension, in athletes, and so on. Left ventricle hypertrophy may also be associated with a change in the actual structure: for example, with hypertrophic cardiomyopathy.Signs of left ventricle hypertrophy by echocardiography are a very significant predictor of mortality in patients with arterial hypertension in the general population. The presence of left ventricle hypertrophy by echocardiography is a high cardiovascular risk for the patient.It is important to diagnose diseases with a high risk of sudden cardiac death on time. One of these diseases is hypertrophic cardiomyopathy. A clinical diagnosis of hypertrophic cardiomyopathy is impossible without visualization. Therefore, the European Association of Cardiovascular Imaging recommends a multimodal approach in examining patients with hypertrophic cardiomyopathy.Сomputed tomography, echocardiography, and magnetic resonance imaging are used to diagnose which patient’s hypertrophy is pathological or physiological. The choice of which method to use depends on the diagnostic task, and also on the specific advantages and disadvantages of the method. Different visualization methods should be considered complementary, not competing. It is also important to choose a particular imaging technique given its diagnostic value, availability, benefits, risks and costs.
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Yalçin, Fatih, Nagehan Kucukler, Oscar Cingolani, Blaid Mbiyangandu, Lars Sorensen, Aurelio Pinherio, M. Roselle Abraham i Theodore P. Abraham. "Evolution of ventricular hypertrophy and myocardial mechanics in physiological and pathological hypertrophy". Journal of Applied Physiology 126, nr 2 (1.02.2019): 354–62. http://dx.doi.org/10.1152/japplphysiol.00199.2016.
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Left ventricular hypertrophy (LVH) is an adaptive response to physiological or pathological stimuli, and distinguishing between the two has obvious clinical implications. However, asymmetric septal hypertrophy and preserved cardiac function are noted in early stages in both cases. We characterized the early anatomic and functional changes in a mouse model of physiological and pathological stress using serial echocardiography-based morphometry and tissue velocity imaging. Weight-matched CF-1 male mice were separated into Controls ( n = 10), treadmill Exercise 1 h daily for 5 days/wk ( n = 7), and transverse aortic constriction (TAC, n = 7). Hypertrophy was noted first in the left ventricle basal septum compared with other segments in Exercise (0.84 ± 0.02 vs. 0.79 ± 0.03 mm, P = 0.03) and TAC (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02) at 4 and 3 wk, respectively. At 8 wk, eccentric LVH was noted in Exercise and concentric LVH in TAC. Septal E/E′ ratio increased in TAC (32.6 ± 3.7 vs. 37 ± 6.2, P = 0.002) compared with the Controls and Exercise (32.3 ± 5.2 vs. 32.8 ± 3.8 and 31.2 ± 4.9 vs. 28.2 ± 5.0, respectively, nonsignificant for both). Septal s′ decreased in TAC (21 ± 3.6 vs. 17 ± 4.2 mm/s, P = 0.04) but increased in Exercise (19.6 ± 4.1 vs. 29.2 ± 2.3 mm/s, P = 0.001) and was unchanged in Controls (20.1 ± 4.2 vs. 20.9 ± 5.1 mm/s, nonsignificant). With similar asymmetric septal hypertrophy and normal global function during the first 4–8 wk of pathological and physiological stress, there is an early marginal increase with subsequent decrease in systolic tissue velocity in pathological but early and progressive increase in physiological hypertrophy. Tissue velocities may help adjudicate between these two states when there are no overt anatomic or functional differences. NEW & NOTEWORTHY Pathological and physiological stress-induced ventricular hypertrophy have different clinical connotations but present with asymmetric septal hypertrophy and normal global function in their early stages. We observed a marginal but statistically significant decrease in systolic tissue velocity in pathological but progressive increase in velocity in physiological hypertrophy. Tissue velocity imaging could be an important tool in the management of asymmetric septal hypertrophy by adjudicating between these two etiologies when there are no overt anatomic or functional differences.
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Gesmundo, Iacopo, Michele Miragoli, Pierluigi Carullo, Letizia Trovato, Veronica Larcher, Elisa Di Pasquale, Mara Brancaccio i in. "Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure". Proceedings of the National Academy of Sciences 114, nr 45 (25.10.2017): 12033–38. http://dx.doi.org/10.1073/pnas.1712612114.
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It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.
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Peng, Shi, Xiao-feng Lu, Yi-ding Qi, Jing Li, Juan Xu, Tian-you Yuan, Xiao-yu Wu i in. "LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway". Oxidative Medicine and Cellular Longevity 2020 (18.09.2020): 1–15. http://dx.doi.org/10.1155/2020/9815039.
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Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.
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Gallo, Simona, Annapia Vitacolonna, Alessandro Bonzano, Paolo Comoglio i Tiziana Crepaldi. "ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy". International Journal of Molecular Sciences 20, nr 9 (1.05.2019): 2164. http://dx.doi.org/10.3390/ijms20092164.
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Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context.
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Dobrzyn, Pawel, Aleksandra Pyrkowska, Monika K. Duda, Tomasz Bednarski, Michal Maczewski, Jozef Langfort i Agnieszka Dobrzyn. "Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy". American Journal of Physiology-Endocrinology and Metabolism 304, nr 12 (15.06.2013): E1348—E1358. http://dx.doi.org/10.1152/ajpendo.00603.2012.
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Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-α (PPARα) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARα and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser565, and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future.
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Li, Haobo, Lena E. Trager, Xiaojun Liu, Margaret H. Hastings, Chunyang Xiao, Justin Guerra, Samantha To i in. "lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth". Circulation 145, nr 16 (19.04.2022): 1218–33. http://dx.doi.org/10.1161/circulationaha.121.056850.
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Background: The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis. Methods: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid–GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice. Results: We identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis. Conclusions: These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.
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Piven, O. O. "Signalling function of β-catenin is important at early stages of adult heart pathological hypertrophy". Visnik ukrains'kogo tovaristva genetikiv i selekcioneriv 14, nr 1 (20.06.2016): 44–51. http://dx.doi.org/10.7124/visnyk.utgis.14.1.543.
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The spread of cardiovascular diseases, their significant threat to health and socio-economic burden result in considerable interest of scientists to this problem solution. Lately, not only investigations into new methods of diagnosis and treatment of cardiovascular disease, but also elucidation of the mechanisms underlying their occurrence and course become topical. The aim of our study was to investigate the signaling function of the canonical Wnt-signaling and b-catenin function in the development of pathological hypertrophy of the adult myocardium. Methods. Studies were conducted using transgenic mice BATGIRL and cultures of isolated cardiomyocytes. To induce pathological hypertrophy, lithium chloride and AnglI were used. Changes in the expression of hypertrophic genes and genes involved in the canonical Wnt-signaling were analyzed by real-time PCR and Western-blot analysis. Morphological studies and X-gal staining were performed. Results. Upon the action of hypertrophic stimuli the activation of b-catenin signaling function is shown to occur in the early stages of observation, as evidenced by X-gal staining and changes in gene-targets expression of this signaling (c-Fos, c-Myc, CyclinD1 and TCF-4). There was also observed an increase in the content of activated b-catenin and phosphorylated GSK3b proteins within a day after the action of angiotensin and lithium chloride in the culture of isolated cardiomyocytes. Conclusions. With the development of pathological hypertrophy due to chronic high blood pressure, there occurs the activation of many signal-regulatory mechanisms of cardiomyocytes and one of them is the canonical Wnt-signaling. However, the activation of the canonical Wnt-signaling and β-catenin, in particular, is the early event and obviously essential to run the genetic program of myocardium remodeling.Keywords: β-catenin, hypertrophy, Wnt-signaling, gene expression, myocardium.
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Ren, Zongna, Peng Yu, Dandan Li, Zheng Li, Yingnan Liao, Yin Wang, Bingying Zhou i Li Wang. "Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy". Circulation 141, nr 21 (26.05.2020): 1704–19. http://dx.doi.org/10.1161/circulationaha.119.043053.
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Background: Pressure overload–induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart’s workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type–specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels. Methods: By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload–induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo. Results: We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure. Conclusions: Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.
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Liu, Yaoqiu, Yahui Shen, Jingai Zhu, Ming Liu, Xing Li, Yumei Chen, Xiangqing Kong, Guixian Song i Lingmei Qian. "Cardiac-Specific PID1 Overexpression Enhances Pressure Overload-Induced Cardiac Hypertrophy in Mice". Cellular Physiology and Biochemistry 35, nr 5 (2015): 1975–85. http://dx.doi.org/10.1159/000374005.
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Background/Aims: PID1 was originally described as an insulin sensitivity relevance protein, which is also highly expressed in heart tissue. However, its function in the heart is still to be elucidated. Thus this study aimed to investigate the role of PID1 in the heart in response to hypertrophic stimuli. Methods: Samples of human failing hearts from the left ventricles of dilated cardiomyopathy (DCM) patients undergoing heart transplants were collected. Transgenic mice with cardiomyocyte-specific overexpression of PID1 were generated, and cardiac hypertrophy was induced by transverse aortic constriction (TAC). The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. Results: A significant increase in PID1 expression was observed in failing human hearts and TAC-treated wild-type mouse hearts. When compared with TAC-treated wild-type mouse hearts, PID1-TG mouse showed a significant exacerbation of cardiac hypertrophy, fibrosis, and dysfunction. Further analysis of the signaling pathway in vivo suggested that these adverse effects of PID1 were associated with the inhibition of AKT, and activation of MAPK pathway. Conclusion: Under pathological conditions, over-expression of PID1 promotes cardiac hypertrophy by regulating the Akt and MAPK pathway.
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Li, Jin, Zhao Sha, Xiaolan Zhu, Wanru Xu, Weilin Yuan, Tingting Yang, Bing Jin i in. "Targeting miR-30d reverses pathological cardiac hypertrophy". eBioMedicine 81 (lipiec 2022): 104108. http://dx.doi.org/10.1016/j.ebiom.2022.104108.
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Li, Zhenhua, Jian Wang i Xiao Yang. "Functions of Autophagy in Pathological Cardiac Hypertrophy". International Journal of Biological Sciences 11, nr 6 (2015): 672–78. http://dx.doi.org/10.7150/ijbs.11883.
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