Journal articles: 'Cardiac hypoxia reoxygenation'

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Zarndt, Rachel, Sarah Piloto, Frank L. Powell, Gabriel G. Haddad, Rolf Bodmer, and Karen Ocorr. "Cardiac responses to hypoxia and reoxygenation in Drosophila." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 11 (December 1, 2015): R1347—R1357. http://dx.doi.org/10.1152/ajpregu.00164.2015.

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An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation.

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Kehrer, J. P., Y. Park, and H. Sies. "Energy dependence of enzyme release from hypoxic isolated perfused rat heart tissue." Journal of Applied Physiology 65, no. 4 (October 1, 1988): 1855–60. http://dx.doi.org/10.1152/jappl.1988.65.4.1855.

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There is a sudden release of intracellular constituents upon reoxygenation of isolated perfused hypoxic heart tissue (O2 paradox) or on perfusion with calcium-free medium after a period of hypoxia. Rat hearts were perfused by the method of Langendorff (Pfluegers Arch. 61: 291-332, 1895) with Krebs-Henseleit medium containing 10 mM glucose. Hearts were equilibrated for 30 min, followed by 90 min of hypoxia or 60 min of hypoxia and 30 min of reoxygenation. The massive enzyme release observed upon reoxygenation after 60 min of hypoxia was prevented by infusing 0.5 or 5 mM cyanide 5 min before reoxygenation. Lactate dehydrogenase (LDH) release commenced immediately upon withdrawal of cyanide. Hearts perfused with calcium-free medium throughout hypoxia did not release increased amounts of LDH at reoxygenation. Perfusing heart tissue with medium containing 0 or 25 microM calcium, but not 0.25 or 2.5 mM, after 50 min of hypoxia initiated a release of cardiac LDH, which was not further enhanced by reoxygenation. Enzyme release was significantly inhibited when the calcium-free perfusion medium included 10 mM 2-deoxyglucose (replacing glucose), 0.5 mM dinitrophenol, or 2.5 mM cyanide. Histologically, hearts perfused with calcium-free medium after 50 min of hypoxia showed areas of severe necrosis and contracture without any evidence of the contraction bands that were seen in hearts reoxygenated in the presence of calcium. Cardiac ATP and creatine phosphate (PCr) levels were significantly decreased after 50-60 min of hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

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Kapelko, Valery I., Vladimir L. Lakomkin, Alexander A. Abramov, Elena V. Lukoshkova, Nidas A. Undrovinas, Asker Y. Khapchaev, and Vladimir P. Shirinsky. "Protective Effects of Dinitrosyl Iron Complexes under Oxidative Stress in the Heart." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/9456163.

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Background. Nitric oxide can successfully compete with oxygen for sites of electron-transport chain in conditions of myocardial hypoxia. These features may prevent excessive oxidative stress occurring in cardiomyocytes during sudden hypoxia-reoxygenation.Aim. To study the action of the potent stable NO donor dinitrosyl iron complex with glutathione (Oxacom®) on the recovery of myocardial contractile function and Ca2+transients in cardiomyocytes during hypoxia-reoxygenation.Results. The isolated rat hearts were subjected to 30 min hypoxia followed by 30 min reoxygenation. The presence of 30 nM Oxacom in hypoxic perfusate reduced myocardial contracture and improved recovery of left ventricular developed pressure partly due to elimination of cardiac arrhythmias. The same Oxacom concentration limited reactive oxygen species generation in hypoxic cardiomyocytes and increased the viability of isolated cardiomyocytes during hypoxia from 12 to 52% and after reoxygenation from 0 to 40%. Oxacom prevented hypoxia-induced elevation of diastolic Ca2+level and eliminated Ca2+transport alterations manifested by slow Ca2+removal from the sarcoplasm and delay in cardiomyocyte relaxation.Conclusion. The potent stable NO donor preserved cardiomyocyte integrity and improved functional recovery at hypoxia-reoxygenation both in the isolated heart and in cardiomyocytes mainly due to preservation of Ca2+transport. Oxacom demonstrates potential for cardioprotection during hypoxia-reoxygenation.

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Şimşek, Gül, and Hilmi Burak Kandilci. "Hypoxia-Reoxygenation Induced Cardiac Mitochondrial Dysfunction." Journal of Ankara University Faculty of Medicine 71, no. 3 (December 1, 2018): 139–44. http://dx.doi.org/10.4274/atfm.29863.

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Boslett, James, Craig Hemann, Fedias L. Christofi, and Jay L. Zweier. "Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion." American Journal of Physiology-Cell Physiology 314, no. 3 (March 1, 2018): C297—C309. http://dx.doi.org/10.1152/ajpcell.00139.2017.

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The NAD(P)+-hydrolyzing enzyme CD38 is activated in the heart during the process of ischemia and reperfusion, triggering NAD(P)(H) depletion. However, the presence and role of CD38 in the major cell types of the heart are unknown. Therefore, we characterize the presence and function of CD38 in cardiac myocytes, endothelial cells, and fibroblasts. To comprehensively evaluate CD38 in these cells, we measured gene transcription via mRNA, as well as protein expression and enzymatic activity. Endothelial cells strongly expressed CD38, while only low expression was present in cardiac myocytes with intermediate levels in fibroblasts. In view of this high level expression in endothelial cells and the proposed role of CD38 in the pathogenesis of endothelial dysfunction, endothelial cells were subjected to hypoxia-reoxygenation to characterize the effect of this stress on CD38 expression and activity. An activity-based CD38 imaging method and CD38 activity assays were used to characterize CD38 activity in normoxic and hypoxic-reoxygenated endothelial cells, with marked CD38 activation seen following hypoxia-reoxygenation. To test the impact of hypoxia-reoxygenation-induced CD38 activation on endothelial cells, NAD(P)(H) levels and endothelial nitric oxide synthase (eNOS)-derived NO production were measured. Marked NADP(H) depletion with loss of NO and increase in superoxide production occurred following hypoxia-reoxygenation that was prevented by CD38 inhibition or knockdown. Thus, endothelial cells have high expression of CD38 which is activated by hypoxia-reoxygenation triggering CD38-mediated NADP(H) depletion with loss of eNOS-mediated NO generation and increased eNOS uncoupling. This demonstrates the importance of CD38 in the endothelium and explains the basis by which CD38 triggers post-ischemic endothelial dysfunction.

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Ning, Xue-Han, Shi-Han Chen, Cheng-Su Xu, Outi M. Hyyti, Kun Qian, Julia J. Krueger, and Michael A. Portman. "Hypothermia preserves myocardial function and mitochondrial protein gene expression during hypoxia." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H212—H219. http://dx.doi.org/10.1152/ajpheart.01149.2002.

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Hypothermia before and/or during no-flow ischemia promotes cardiac functional recovery and maintains mRNA expression for stress proteins and mitochondrial membrane proteins (MMP) during reperfusion. Adaptation and protection may occur through cold-induced change in anaerobic metabolism. Accordingly, the principal objective of this study was to test the hypothesis that hypothermia preserves myocardial function during hypoxia and reoxygenation. Hypoxic conditions in these experiments were created by reducing O2 concentration in perfusate, thereby maintaining or elevating coronary flow (CF). Isolated Langendorff-perfused rabbit hearts were subjected to perfusate (Po2 = 38 mmHg) with glucose (11.5 mM) and perfusion pressure (90 mmHg). The control (C) group was at 37°C for 30 min before and 45 min during hypoxia, whereas the hypothermia (H) group was at 29.5°C for 30 min before and 45 min during hypoxia. Reoxygenation occurred at 37°C for 45 min for both groups. CF increased during hypoxia. The H group markedly improved functional recovery during reoxygenation, including left ventricular developed pressure (DP), the product of DP and heart rate, dP/d tmax, and O2 consumption (MVo2) ( P < 0.05 vs. control). MVo2 decreased during hypothermia. Lactate and CO2 gradients across the coronary bed were the same in C and H groups during hypoxia, implying similar anaerobic metabolic rates. Hypothermia preserved MMP βF1-ATPase mRNA levels but did not alter adenine nucleotide translocator-1 or heat shock protein-70 mRNA levels. In conclusion, hypothermia preserves cardiac function after hypoxia in the hypoxic high-CF model. Thus hypothermic protection does not occur exclusively through cold-induced alterations in anaerobic metabolism.

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Wagner, Kay-Dietrich, Vanja Essmann, Karsten Mydlak, Manfred Wirth, Gunnar Gmehling, Jürgen Bohlender, Harald M. Stauss, Joachim Günther, Ingolf Schimke, and Holger Scholz. "Decreased susceptibility of cardiac function to hypoxia-reoxygenation in renin-angiotensinogen transgenic rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 1 (July 1, 2002): R153—R160. http://dx.doi.org/10.1152/ajpregu.00491.2001.

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We tested the hypothesis that the renin-angiotensin system (RAS) protects the contractile function of the myocardium against the damaging effect of hypoxia-reoxygenation. For this purpose, the contractility of isolated papillary muscles from wild-type (WT) rats and from rats expressing human renin and angiotensinogen as transgenes (TGR) was compared. After 15 min of hypoxia, peak force (PF) was decreased to 24 ± 5% of the normoxic values in TGR ( n = 10) and to 18 ± 1% in WT rats ( n = 12). PF and relaxation rates recovered completely in TGR but not in WT rats during 45 min of reoxygenation. Improved contractility of the papillary muscles from TGR during hypoxia-reoxygenation correlated with increased glutathione peroxidase activities and creatine kinase (CK)-MB and CK-BB isoenzyme levels. On the other hand, inhibition of the RAS with ramipril (1 mg/kg body wt for 3 wk) in WT animals resulted in deterioration of the contractile function of the papillary muscles during reoxygenation compared with untreated rats. These findings suggest that activation of the RAS protects contractile function of the cardiac muscle against hypoxia-reoxygenation, possibly through changes in CK isoenzymes and enhanced antioxidant capacity.

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Ilyas, Ermita I. Ibrahim, Busjra M. Nur, Sonny P. Laksono, Anton Bahtiar, Ari Estuningtyas, Caecilia Vitasyana, Dede Kusmana, Frans D. Suyatna, Muhammad Kamil Tadjudin, and Hans-Joachim Freisleben. "Effects of Curcumin on Parameters of Myocardial Oxidative Stress and of Mitochondrial Glutathione Turnover in Reoxygenation after 60 Minutes of Hypoxia in Isolated Perfused Working Guinea Pig Hearts." Advances in Pharmacological Sciences 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/6173648.

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In cardiovascular surgery ischemia-reperfusion injury is a challenging problem, which needs medical intervention. We investigated the effects of curcumin on cardiac, myocardial, and mitochondrial parameters in perfused isolated working Guinea pig hearts. After preliminary experiments to establish the model, normoxia was set at 30 minutes, hypoxia was set at 60, and subsequent reoxygenation was set at 30 minutes. Curcumin was applied in the perfusion buffer at 0.25 and 0.5 μM concentrations. Cardiac parameters measured were afterload, coronary and aortic flows, and systolic and diastolic pressure. In the myocardium histopathology and AST in the perfusate indicated cell damage after hypoxia and malondialdehyde (MDA) levels increased to 232.5% of controls during reoxygenation. Curcumin protected partially against reoxygenation injury without statistically significant differences between the two dosages. Mitochondrial MDA was also increased in reoxygenation (165% of controls), whereas glutathione was diminished (35.2%) as well as glutathione reductase (29.3%), which was significantly increased again to 62.0% by 0.05 μM curcumin. Glutathione peroxidase (GPx) was strongly increased in hypoxia and even more in reoxygenation (255% of controls). Curcumin partly counteracted this increase and attenuated GPx activity independently in hypoxia and in reoxygenation, 0.25 μM concentration to 150% and 0.5 μM concentration to 200% of normoxic activity.

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Battiprolu, Pavan K., and Kenneth J. Rodnick. "Dichloroacetate selectively improves cardiac function and metabolism in female and male rainbow trout." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 10 (November 15, 2014): H1401—H1411. http://dx.doi.org/10.1152/ajpheart.00755.2013.

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Cardiac tissue from female rainbow trout demonstrates a sex-specific preference for exogenous glucose and glycolysis, impaired Ca2+ handling, and a greater tolerance for hypoxia and reoxygenation than cardiac tissue from male rainbow trout. We tested the hypothesis that dichloroacetate (DCA), an activator of pyruvate dehydrogenase, enhances cardiac energy metabolism and Ca2+ handling in female preparations and provide cardioprotection for hypoxic male tissue. Ventricle strips from sexually immature fish with very low (male) and nondetectable (female) plasma sex steroids were electrically paced in oxygenated or hypoxic Ringer solution with or without 1 mM DCA. In the presence of 5 mM glucose, aerobic tissue from male trout could be paced at a higher frequency (1.79 vs. 1.36 Hz) with lower resting tension and less contractile dysfunction than female tissue. At 0.5 Hz, DCA selectively reduced resting tension below baseline values and lactate efflux by 75% in aerobic female ventricle strips. DCA improved the functional recovery of developed twitch force, reduced lactate efflux by 50%, and doubled citrate in male preparations after hypoxia-reoxygenation. Independent of female sex steroids, reduced myocardial pyruvate dehydrogenase activity and impaired carbohydrate oxidation might explain the higher lactate efflux, compromised function of the sarcoplasmic reticulum, and reduced mechanical performance of aerobic female tissue. Elevated oxidative metabolism and reduced glycolysis might also underlie the beneficial effects of DCA on the mechanical recovery of male cardiac tissue after hypoxia-reoxygenation. These results support the use of rainbow trout as an experimental model of sex differences of cardiovascular energetics and function, with the potential for modifying metabolic phenotypes and cardioprotection independent of sex steroids.

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Endoh, Hiroshi, Takaho Kaneko, Hiro Nakamura, Katsuhiko Doi, and Eiji Takahashi. "Improved cardiac contractile functions in hypoxia-reoxygenation in rats treated with low concentration Co2+." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 6 (December 1, 2000): H2713—H2719. http://dx.doi.org/10.1152/ajpheart.2000.279.6.h2713.

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An intracellular mechanism that senses decreases in tissue oxygen level and stimulates hypoxia-related gene expression has been reported in various cell types including the cardiac cell. The mechanism can also be activated by Co2+ in normoxia. Thus we investigated the effects of prior chronic oral CoCl2 on mechanical functions of isolated, perfused rat hearts in hypoxia-reoxygenation. In normoxic rats, 43 days of Co2+ administration increased hematocrit from 45 ± 0.3% (control, n = 18) to 51 ± 0.6% ( n = 19). In hypoxia and reoxygenation, Co2+-pretreated hearts exhibited a significantly higher rate-pressure product (267 and 163%, respectively) and coronary flow (127 and 118%, respectively) and lower end-diastolic pressure (72 and 60%, respectively) compared with the control hearts. Although the oral Co2+ administration significantly raised myocardial Co2+ concentration, it did not affect mitochondrial respiration, tissue glycogen concentration, or myocardial tissue histology. The levels of vascular endothelial growth factor, aldolase-A, and glucose transporter-1 mRNA were significantly elevated in the Co2+-treated myocardium. We conclude that cardiac contractile functions would gain hypoxic tolerance when the endogenous cellular oxygen-sensing mechanism is activated.

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Sharikabad, Mohammad Nouri, Jan Magnus Aronsen, Espen Haugen, Janne Pedersen, Anne-Sophie W. Møller, Halvor Kjeang Mørk, Hans C. D. Aass, Ole M. Sejersted, Ivar Sjaastad, and Odd Brørs. "Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 3 (March 2009): H787—H795. http://dx.doi.org/10.1152/ajpheart.00796.2008.

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Altered myocardial Ca2+ and Na+ handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca2+ overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca2+ and Na+ in cardiomyocytes from failing rat hearts. CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 wk. Isolated cardiomyocytes were cultured for 24 h and subsequently exposed to 4 h of hypoxia and 2 h of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firefly luciferase assay. Cell Ca2+ and Na+ were determined with radioactive isotopes, and free intracellular Ca2+ concentration ([Ca2+]i) with fluo-3 AM. CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than sham cells. CHF cells accumulated less Na+ than sham cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca2+]i than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca2+ increased much less in CHF than in sham cells (1.4 vs. 6.7 nmol/mg protein) after 120 min of reoxygenation. Ranolazine, an inhibitor of late Na+ current, significantly attenuated both the increase in exchangeable Ca2+ and the increase in LD release in sham cells after reoxygenation. This supports the suggestion that differences in Na+ accumulation during hypoxia cause the observed differences in Ca2+ accumulation during reoxygenation. Tolerance to hypoxia and reoxygenation was surprisingly higher in CHF than in sham cardiomyocytes, probably explained by lower hypoxia-mediated Na+ accumulation and subsequent lower Ca2+ accumulation in CHF after reoxygenation.

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Buerke, M., A. S. Weyrich, and A. M. Lefer. "Isolated cardiac myocytes are sensitized by hypoxia-reoxygenation to neutrophil-released mediators." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 1 (January 1, 1994): H128—H136. http://dx.doi.org/10.1152/ajpheart.1994.266.1.h128.

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We exposed isolated rat cardiac myocytes to 20 min of hypoxia followed by 20 min of reoxygenation and observed the effect of supernatants of stimulated neutrophils [polymorphonuclear leukocytes (PMNs)] given at the beginning of reoxygenation. PMN supernatants induced cardiac myocyte injury, which was characterized by a significant (P < 0.01) reduction in cell viability to 53 +/- 3%, vs. 84 +/- 3% in rat myocytes subjected to hypoxia-reoxygenation (H/R) alone. The PMN supernatants also resulted in elevated creatine kinase (CK) activities in the myocyte medium. To examine specific PMN-released mediators that may contribute to this cell death, we studied the effects of hydrogen peroxide (H2O2), elastase, and platelet-activating factor on H/R cardiac myocytes. Incubation of myocytes after hypoxia with 10, 50, and 100 microM H2O2 decreased viability in a concentration-dependent manner (from 83 +/- 2 to 37 +/- 2%; P < 0.01). CK release of H/R myocytes was also significantly increased by 100 microM H2O2 (to 28 +/- 5 from 12 +/- 1% for H/R alone; P < 0.01). Similarly, elastase (5 micrograms/ml) given after hypoxia significantly reduced cardiac myocyte viability during reoxygenation (viability 58 +/- 1 vs. 85 +/- 1% H/R alone; P < 0.05) and increased CK release (to 29 +/- 3 from 11 +/- 1% for H/R alone; P < 0.01), an effect that was abolished by L-680,833, an elastase inhibitor. Unlike H2O2 and elastase, platelet-activating factor had no significant effect on myocyte viability or CK release after H/R.(ABSTRACT TRUNCATED AT 250 WORDS)

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Eigel, B. N., H. Gursahani, and R. W. Hadley. "ROS are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 3 (March 2004): H955—H963. http://dx.doi.org/10.1152/ajpheart.00721.2003.

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The cardiac Na+/Ca2+ exchanger (NCX) contributes to cellular injury during hypoxia, as its altered function is largely responsible for a rise in cytosolic Ca2+ concentration ([Ca2+]i). In addition, the NCX in guinea pig ventricular myocytes undergoes profound inhibition during hypoxia and rapid reactivation during reoxygenation. The mechanisms underlying these changes in NCX activity are likely complex due to the participation of multiple inhibitory factors including altered cytosolic Na+ concentration, pH, and ATP. Our main hypothesis is that oxidative stress is an essential trigger for rapid NCX reactivation in guinea pig ventricular myocytes and is thus a critical factor in determining the timing and magnitude of Ca2+ overload. This hypothesis was evaluated in cardiac myocytes using fluorescent indicators to measure [Ca2+]i and oxidative stress. An NCX antisense oligonucleotide was used to decrease NCX protein expression in some experiments. Our results indicate that NCX activity is profoundly inhibited in hypoxic guinea pig ventricular myocytes but is reactivated within 1–2 min of reoxygenation at a time of rising oxidative stress. We also found that several interventions to decrease oxidative stress including antioxidants and diazoxide prevented NCX reactivation and Ca2+ overload during reoxygenation. Furthermore, application of exogenous H2O2 was sufficient by itself to reactivate the NCX during sustained hypoxia and could reverse the suppression of reoxygenation-mediated NCX reactivation by diazoxide. These data suggest that elevated oxidative stress in reoxygenated guinea pig ventricular myocytes is required for rapid NCX reactivation, and thus reactivation should be viewed as an active process rather than being due to the simple decline of NCX inhibition.

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Eigel, B. N., H. Gursahani, and R. W. Hadley. "Na+/Ca2+ exchanger plays a key role in inducing apoptosis after hypoxia in cultured guinea pig ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 4 (October 2004): H1466—H1475. http://dx.doi.org/10.1152/ajpheart.00874.2003.

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Altered Na+/Ca2+ exchanger (NCX) protein expression or activity is thought to contribute to various aspects of cardiac pathology. In guinea pig ventricular myocytes, NCX-mediated Ca2+ entry is almost entirely responsible for Ca2+ overload during hypoxia-reoxygenation. Because Ca2+ overload is a common initiator of apoptosis, the purpose of this study was to test the hypotheses that NCX activity is critically involved in initiating apoptosis after hypoxia-reoxygenation and that hypoxia-reoxygenation-induced apoptosis can be modulated by changes in NCX protein expression or activity. An NCX antisense oligonucleotide was used to reduce NCX protein expression in cultured adult guinea pig ventricular myocytes. Caspase-3 activation and cytochrome c release were used as markers of apoptosis. Hypoxia-reoxygenation-induced apoptosis was significantly decreased in antisense-treated myocytes compared with untreated control or nonsense-treated myocytes. Pretreatment of cultured myocytes for 24 h with either endothelin-1 or phenylephrine was found to increase both NCX protein expression and evoked NCX activity as well as enhance hypoxia-reoxygenation-induced apoptosis. Control experiments demonstrated that endothelin-1 and phenylephrine did not induce apoptosis on their own nor did they enhance the apoptotic response in a model of Ca2+-dependent, NCX-independent apoptosis. Additional control experiments demonstrated that the NCX antisense oligonucleotide did not alter the apoptotic response of myocytes to either H2O2 or isoproterenol. Taken together, these data suggest that the NCX has a critical and specific role in the initiation of apoptosis after hypoxia-reoxygenation in guinea pig myocytes and that hypoxia-reoxygenation-induced apoptosis is quite sensitive to changes in NCX activity.

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Ruhr, Ilan M., Heather McCourty, Afaf Bajjig, Dane A. Crossley, Holly A. Shiels, and Gina L. J. Galli. "Developmental plasticity of cardiac anoxia-tolerance in juvenile common snapping turtles ( Chelydra serpentina )." Proceedings of the Royal Society B: Biological Sciences 286, no. 1905 (June 26, 2019): 20191072. http://dx.doi.org/10.1098/rspb.2019.1072.

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For some species of ectothermic vertebrates, early exposure to hypoxia during embryonic development improves hypoxia-tolerance later in life. However, the cellular mechanisms underlying this phenomenon are largely unknown. Given that hypoxic survival is critically dependent on the maintenance of cardiac function, we tested the hypothesis that developmental hypoxia alters cardiomyocyte physiology in a manner that protects the heart from hypoxic stress. To test this hypothesis, we studied the common snapping turtle, which routinely experiences chronic developmental hypoxia and exploits hypoxic environments in adulthood. We isolated cardiomyocytes from juvenile turtles that embryonically developed in either normoxia (21% O 2 ) or hypoxia (10% O 2 ), and subjected them to simulated anoxia and reoxygenation, while simultaneously measuring intracellular Ca 2+ , pH and reactive oxygen species (ROS) production. Our results suggest developmental hypoxia improves cardiomyocyte anoxia-tolerance of juvenile turtles, which is supported by enhanced myofilament Ca 2+ -sensitivity and a superior ability to suppress ROS production. Maintenance of low ROS levels during anoxia might limit oxidative damage and a greater sensitivity to Ca 2+ could provide a mechanism to maintain contractile force. Our study suggests developmental hypoxia has long-lasting effects on turtle cardiomyocyte function, which might prime their physiology for exploiting hypoxic environments.

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Seki, S., and K. T. MacLeod. "Effects of anoxia on intracellular Ca2+ and contraction in isolated guinea pig cardiac myocytes." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 3 (March 1, 1995): H1045—H1052. http://dx.doi.org/10.1152/ajpheart.1995.268.3.h1045.

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Single, enzymatically isolated guinea pig ventricular myocytes were exposed to 3-min periods of anoxia with glucose-free Tyrode solution containing 1 mM sodium dithionite (Na2S2O4) and were then reoxygenated for 10 min. The myocytes were exposed to rapid applications of 10 mM caffeine during the control, anoxic, and reoxygenation periods. Intracellular Ca2+ concentration ([Ca2+]i) was measured ratiometrically using indo 1 with simultaneous measurements of cell length. The effects of anoxia on Ca2+ were compared with those of hypoxia and metabolic inhibition. The amplitude of the electrically stimulated (Ca transient) and caffeine-evoked Ca2+ (Caff-Ca) transients decreased during anoxia and recovered after reoxygenation. Diastolic [Ca2+]i did not change during 3 min of anoxia but rose progressively after prolonged anoxia and remained at this higher level on reoxygenation. During metabolic inhibition the Ca transients decreased, while the Caff-Ca transients showed no change in amplitude. During hypoxia the Ca transients decreased. Anoxia slowed the time to peak of the Ca transient, the time to 50% relaxation, and the time to 90% relaxation. The decline of indo 1 fluorescence on rapid caffeine application was slowed during anoxia, metabolic inhibition, and hypoxia and partially recovered after reoxygenation.

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Marsh, J. D., and K. A. Sweeney. "Beta-adrenergic receptor regulation during hypoxia in intact cultured heart cells." American Journal of Physiology-Heart and Circulatory Physiology 256, no. 1 (January 1, 1989): H275—H281. http://dx.doi.org/10.1152/ajpheart.1989.256.1.h275.

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Regulation of cardiac beta-adrenergic receptors during hypoxia and ischemia is an area of active investigation, with some investigators reporting an increase in sarcolemmal beta-receptor number after ischemia. Previous studies have been limited by the necessity of examining beta-adrenergic receptor properties in membrane preparations from hypoxic or ischemic cardiac tissue and drawing conclusions about receptor localization in intact tissue from the behavior of a fraction of total receptors in membrane populations. As an approach to examining beta-receptor properties under well-defined pathophysiological conditions in intact heart cells, we studied cell-surface beta-receptors and adenylate cyclase activity in intact cultured chick embryo ventricular cells under conditions of controlled hypoxia and reoxygenation. During 2 h of hypoxia (PO2 less than 1.5 Torr) there was a progressive decline in cell surface beta-receptors from 26 +/- 2 to 10 +/- 6 fmol/mg (P less than 0.003) with no change in antagonist or agonist affinity. Receptor number recovered fully during 2 h of reoxygenation. Basal adenosine 3',5'-cyclic monophosphate (cAMP) production was unchanged, but response to isoproterenol in the absence or presence of a phosphodiesterase inhibitor decreased to about half of the response for normoxic cells but fully recovered during reoxygenation in a pattern similar to that for receptor number. Although [ATP] declined significantly during hypoxia (from 35 to 25 nmol/mg), the decline in [GTP] was marginal (4.3 to 3.9 nmol/mg), making it unlikely that substrate for guanine nucleotide regulatory protein was limiting for beta-adrenergic signal transduction.(ABSTRACT TRUNCATED AT 250 WORDS)

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Fantini, Elisabeth, Pierre Athias, Martine Courtois, Shorheh Khatami, Alain Grynberg, and Annick Chevalier. "Oxygen and substrate deprivation on isolated rat cardiac myocytes: temporal relationship between electromechanical and biochemical consequences." Canadian Journal of Physiology and Pharmacology 68, no. 8 (August 1, 1990): 1148–56. http://dx.doi.org/10.1139/y90-172.

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The effects of hypoxia and reoxygenation on action potentials (AP), contractions, and certain biochemical parameters were studied in isolated rat ventricular myocytes in monolayer culture in the presence and absence of glucose. Substrate deprivation alone had no influence on the basal properties. In the presence of glucose, a 4-h hypoxic treatment caused only a moderate decrease in AP amplitude and rate. In substrate-free conditions, hypoxia induced a gradual decline in plateau potential level and in AP duration and rate, followed by rhythm abnormalities and a failure of the electromechanical coupling. Spontaneous AP generation then ceased, and the resting potential decreased with increased duration of hypoxia. These alterations were associated with a decrease in ATP content, an increase in the lactate production, and a leakage of about 50% of the total cellular lactate dehydrogenase (LDH). Cells reoxygenated after 150 min hypoxia recovered near-normal function, while the ATP depletion ceased and the rate of lactate and LDH loss was diminished. Conversely, cells reoxygenated after 4 h hypoxia exhibited a further decrease of the residual resting polarization and no change in the decline of intracellular ATP and in the efflux of cytosolic lactate and LDH. The results of this study indicate that (1) the sequence and the extent of functional alterations are dependent on the duration of hypoxia in the absence of exogenous substrate and (2) ATP depletion and the amount of lactate and LDH released during hypoxia are related to the shift from reversibly to irreversibly damaged cells.Key words: cultured rat cardiomyocytes, electromechanical properties, hypoxia–reoxygenation, glucose deprivation, enzyme release.

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Häkli, Martta, Joose Kreutzer, Antti-Juhana Mäki, Hannu Välimäki, Reeja Maria Cherian, Pasi Kallio, Katriina Aalto-Setälä, and Mari Pekkanen-Mattila. "Electrophysiological Changes of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes during Acute Hypoxia and Reoxygenation." Stem Cells International 2022 (December 19, 2022): 1–15. http://dx.doi.org/10.1155/2022/9438281.

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Ischemic heart disease is the most common cardiovascular disease and a major burden for healthcare worldwide. However, its pathophysiology is still not fully understood, and human-based models for disease mechanisms and treatments are needed. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model acute ischemia-reperfusion in our novel cell culture assembly. The assembly enables exchange of oxygen partial pressure for the cells within minutes, mimicking acute ischemic event. In this study, hypoxia was induced using 0% O2 gas for three hours and reoxygenation with 19% O2 gas for 24 hours in serum- and glucose-free medium. According to electrophysiological recordings, hypoxia decreased the hiPSC-CM-beating frequency and field potential (FP) amplitude. Furthermore, FP depolarization time and propagation slowed down. Most of the electrophysiological changes reverted during reoxygenation. However, immunocytochemical staining of the hypoxic and reoxygenation samples showed that morphological changes and changes in the sarcomere structure did not revert during reoxygenation but further deteriorated. qPCR results showed no significant differences in apoptosis or stress-related genes or in the expression of glycolytic genes. In conclusion, the hiPSC-CMs reproduced many characteristic changes of adult CMs during ischemia and reperfusion, indicating their usefulness as a human-based model of acute cardiac ischemia-reperfusion.

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Yang, Zhao-Kang, Nick J. Draper, and Ajay M. Shah. "Ca2+-independent inhibition of myocardial contraction by coronary effluent of hypoxic rat hearts." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 2 (February 1, 1999): H623—H632. http://dx.doi.org/10.1152/ajpheart.1999.276.2.h623.

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Endothelial cells release agents that influence cardiac contraction. We recently reported that cultured hypoxic endothelial cells release an unidentified factor(s) that inhibits myocardial contraction. In this study, we investigated the effects of coronary effluent of isolated hypoxic rat hearts on isolated rat ventricular myocyte contraction. Coronary effluent collected during brief moderate hypoxia significantly depressed myocyte twitch shortening and decreased diastolic length, with only minor reduction in intracellular Ca2+ transients. These effects were similar to those of hypoxic rat coronary microvascular endothelial cell superfusates and were reversed by reoxygenation of hearts. “Hypoxic” coronary effluent exerted essentially Ca2+-independent effects on myofilament interaction in intact myocytes, as assessed by 1) peak Ca2+-shortening relations, 2) phase-plane analysis of instantaneous Ca2+-cell length relations, and 3) “steady-state” myofilament responses in tetanized, sarcoplasmic reticulum-disabled cells. Thus an unidentified substance(s) that inhibits myocyte shortening predominantly via effects on the myofilaments is reversibly released during acute moderate hypoxia of isolated hearts, presumably from coronary endothelial cells. Release of such an agent may be relevant to the cardiac contractile response to hypoxia.

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DOUGHERTY, Christopher J., Lori A. KUBASIAK, Howard PRENTICE, Peter ANDREKA, Nanette H. BISHOPRIC, and Keith A. WEBSTER. "Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress." Biochemical Journal 362, no. 3 (March 8, 2002): 561–71. http://dx.doi.org/10.1042/bj3620561.

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Reperfusion injury occurs when ischaemic tissue is reperfused. It involves the generation and release of reactive oxygen that activates numerous signalling pathways and initiates cell death. Exposure of isolated cardiac myocytes to chronic hypoxia followed by reoxygenation results in the early activation of c-Jun N-terminal kinase (JNK) and death by apoptosis of approx. 30% of the myocytes. Although JNK activation has been described in a number of models of ischaemia/reperfusion, the contribution of JNK activation to cell fate has not been established. Here we report that the activation of JNK by reoxygenation correlates with myocyte survival. Transfection of myocytes with JNK pathway interfering plasmid vectors or infection with adenoviral vectors support the hypothesis that JNK is protective. Transfection or infection with JNK inhibitory mutants increased the rates of apoptosis by almost 2-fold compared with control cultures grown aerobically or subjected to hypoxia and reoxygenation. Caspase 9 activity, measured by LEHD cleavage, increased > 3-fold during reoxygenation and this activity was enhanced significantly at all times in cultures infected with dominant negative JNK adenovirus. Hypoxia—reoxygenation mediated a biphasic (2.6- and 2.9-fold) activation of p38 mitogen-activated protein kinase, as well as a small increase of tumour necrosis factor α (TNFα) secretion, but treatments with the p38 MAPK-specific inhibitor SB203580 or saturating levels of a TNFα-1 blocking antibody provided only partial protection against apoptosis. The results suggest that JNK activation is protective and that the pathway is largely independent of p38 MAPK or secreted TNFα.

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Sedmera, David, Pavel Kucera, and Eric Raddatz. "Developmental changes in cardiac recovery from anoxia-reoxygenation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 2 (August 1, 2002): R379—R388. http://dx.doi.org/10.1152/ajpregu.00534.2001.

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The developing cardiovascular system is known to operate normally in a hypoxic environment. However, the functional and ultrastructural recovery of embryonic/fetal hearts subjected to anoxia lasting as long as hypoxia/ischemia performed in adult animal models remains to be investigated. Isolated spontaneously beating hearts from Hamburger-Hamilton developmental stages 14( 14HH), 20HH, 24HH, and 27HH chick embryos were subjected in vitro to 30 or 60 min of anoxia followed by 60 min of reoxygenation. Morphological alterations and apoptosis were assessed histologically and by transmission electron microscopy. Anoxia provoked an initial tachycardia followed by bradycardia leading to complete cardiac arrest, except for in the youngest heart, which kept beating. Complete atrioventricular block appeared after 9.4 ± 1.1, 1.7 ± 0.2, and 1.6 ± 0.3 min at stages 20HH, 24HH, and 27HH, respectively. At reoxygenation, sinoatrial activity resumed first in the form of irregular bursts, and one-to-one atrioventricular conduction resumed after 8, 17, and 35 min at stages 20HH, 24HH, and 27HH, respectively. Ventricular shortening recovered within 30 min except at stage 27HH. After 60 min of anoxia, stage 27HHhearts did not retrieve their baseline activity. Whatever the stage and anoxia duration, nuclear and mitochondrial swelling observed at the end of anoxia were reversible with no apoptosis. Thus the embryonic heart is able to fully recover from anoxia/reoxygenation although its anoxic tolerance declines with age. Changes in cellular homeostatic mechanisms rather than in energy metabolism may account for these developmental variations.

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McKean, T., A. Scherzer, and H. Park. "Hypoxia and ischaemia in buffer-perfused toad hearts." Journal of Experimental Biology 200, no. 19 (October 1, 1997): 2575–81. http://dx.doi.org/10.1242/jeb.200.19.2575.

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Previous studies on the effects of ischaemia or hypoxia in ectothermic vertebrate hearts have generally used preparations that were not performing at physiological levels of pressure and flow. The conclusions that ischaemia or hypoxia are not stressful to these organisms were examined in another species, Bufo marinus, in which a buffer-perfused heart was performing physiological levels of work. The in situ preparation demonstrated the Frank-Starling relationship and mechanical characteristics similar to the hearts of intact animals. The hearts recovered from 60 min of ischaemia and reperfusion with no reduction in pressure, flow or heart rate parameters. Hearts exposed to 30 min of hypoxia at physiological filling and diastolic afterload pressures ceased generating a continuous cardiac output during the hypoxia. In most cases, there was a gradual reduction of cardiac output to zero, but in 27% of the hearts studied, intermittent beating was observed. During reoxygenation, the hearts recovered 50-90% of their prehypoxic function and were damaged. Hearts exposed to hypoxia with reduced filling and diastolic afterload continued to develop a cardiac output throughout the hypoxia and demonstrated an overshoot phenomena with the onset of reoxygenation. If demand is in the normal range at the onset of hypoxia, the hearts intrinsically reduce demand either by reducing pressure development or by conversion to intermittent beating. Toad hearts appear not to be damaged by ischaemia, a condition in which demand is low.

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Song, Jong Wook, Hyo Jung Kim, Hyelin Lee, Jae-woo Kim, and Young-Lan Kwak. "Protective Effect of Peroxisome Proliferator-Activated ReceptorαActivation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/3539649.

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Activation of peroxisome proliferator-activated receptorα(PPARα) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPARαactivation against cardiac ischemia-reperfusion injury in terms of the expression of uncoupling protein (UCP). Myocardial infarct size and UCP expression were measured in rats treated with WY-14643 20 mg/kg, a PPARαligand, or vehicle. WY-14643 increased UCP3 expressionin vivo. Myocardial infarct size was decreased in the WY-14643 group (76 ± 8% versus 42 ± 12%,P<0.05). During reperfusion, the incidence of arrhythmia was higher in the control group compared with the WY-14643 group (9/10 versus 3/10,P<0.05). H9c2 cells were incubated for 24 h with WY-14643 or vehicle. WY-14643 increased UCP3 expression in H9c2 cells. WY-14643 decreased hypoxia-stimulated ROS production. Cells treated with WY-14643 were more resistant to hypoxia-reoxygenation than the untreated cells. Knocking-down UCP3 by siRNA prevented WY-14643 from attenuating the production of ROS. UCP3 siRNA abolished the effect of WY-14643 on cell viability against hypoxia-reoxygenation. In summary, administration of PPARαagonist WY-14643 mitigated the extent of myocardial infarction and incidence of reperfusion-induced arrhythmia. PPARαactivation conferred cytoprotective effect against hypoxia-reoxygenation. Associated mechanisms involved increased UCP3 expression and resultant attenuation of ROS production.

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Parente, Valeria, Serena Balasso, Giulio Pompilio, Lorena Verduci, Gualtiero I. Colombo, Giuseppina Milano, Uliano Guerrini, et al. "Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart." PLoS ONE 8, no. 1 (January 16, 2013): e53748. http://dx.doi.org/10.1371/journal.pone.0053748.

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Solevåg, A. L., G. M. Schmölzer, and P. Y. Cheung. "Hypoxia – Reoxygenation in neonatal cardiac arrest: Results from experimental models." Seminars in Fetal and Neonatal Medicine 25, no. 2 (April 2020): 101085. http://dx.doi.org/10.1016/j.siny.2020.101085.

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Baccaro, Cecilia, F. Bennardini, Germana Dini, Flavia Franconi, A. Giotti, Rosanna Matucci, and Paola Minuti. "Cardiac hypoxia and subsequent reoxygenation: sensitivity to L-arginine methylester." British Journal of Pharmacology 87, no. 4 (May 1986): 649–56. http://dx.doi.org/10.1111/j.1476-5381.1986.tb14581.x.

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Hasinoff, Brian B. "Dexrazoxane (ICRF-187) Protects Cardiac Myocytes Against Hypoxia-Reoxygenation Damage." Cardiovascular Toxicology 2, no. 2 (2002): 111–18. http://dx.doi.org/10.1385/ct:2:2:111.

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Prentice, H. M., I. A. Moench, Z. T. Rickaway, C. J. Dougherty, K. A. Webster, and H. Weissbach. "MsrA protects cardiac myocytes against hypoxia/reoxygenation induced cell death." Biochemical and Biophysical Research Communications 366, no. 3 (February 2008): 775–78. http://dx.doi.org/10.1016/j.bbrc.2007.12.043.

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30

Pearson, James T. "Cardiac responses to hypoxia and reoxygenation in Drosophila. New insights into evolutionarily conserved gene responses. Focus on “Cardiac responses to hypoxia and reoxygenation inDrosophila”." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 11 (December 1, 2015): R1344—R1346. http://dx.doi.org/10.1152/ajpregu.00419.2015.

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Cunningham, M. J., C. S. Apstein, E. O. Weinberg, and B. H. Lorell. "Deleterious effect of ouabain on myocardial function during hypoxia." American Journal of Physiology-Heart and Circulatory Physiology 256, no. 3 (March 1, 1989): H681—H687. http://dx.doi.org/10.1152/ajpheart.1989.256.3.h681.

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The effect of cardiac glycosides on myocardial function during hypoxia is controversial. Accordingly, we studied left ventricular performance during hypoxia and reoxygenation in the presence of a mildly inotropic, nontoxic dose of ouabain using isolated, isovolumic, buffer-perfused rabbit hearts. After 15 min of hypoxia, left ventricular developed pressure was less in the ouabain-treated group than in controls (35 +/- 4 vs. 55 +/- 3 mmHg, P less than 0.025). Left ventricular end-diastolic pressure (LVEDP) increased more during hypoxia in the presence of ouabain (9 +/- 1 to 32 +/- 7 with ouabain vs. 9 +/- 1 to 14 +/- 3 mmHg without ouabain, P less than 0.005) despite comparable degrees of coronary vasodilatation and myocardial lactate production in the two groups. When coronary flow was abruptly reduced to zero to eliminate the coronary turgor contribution to diastolic pressure, LVEDP after 15 min of hypoxia in the presence of ouabain was greater than that in control hearts that did not receive ouabain (13 +/- 4 vs. 4 +/- 1 mmHg, P less than 0.05), implicating greater diastolic myocardial fiber tension in the ouabain group during hypoxia. With reoxygenation, recovery of developed pressure was less and end-diastolic pressure remained elevated in the ouabain-treated group when compared with controls. We conclude that a modestly inotropic dose of ouabain exacerbates the decrease in diastolic ventricular distensibility induced by hypoxia, worsens the decline in developed pressure during hypoxia, and impairs recovery during reoxygenation.

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Funcke, Sandra, Tessa R. Werner, Marc Hein, Bärbel M. Ulmer, Arne Hansen, Thomas Eschenhagen, and Marc N. Hirt. "Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study." Biomolecules 10, no. 9 (September 11, 2020): 1309. http://dx.doi.org/10.3390/biom10091309.

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Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** p = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [d-Ala2, d-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, p = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.

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Zeng, Chao, Hu Li, Zhiwen Fan, Lei Zhong, Zhen Guo, Yaping Guo, and Yusheng Xi. "Crocin-Elicited Autophagy Rescues Myocardial Ischemia/Reperfusion Injury via Paradoxical Mechanisms." American Journal of Chinese Medicine 44, no. 03 (January 2016): 515–30. http://dx.doi.org/10.1142/s0192415x16500282.

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Crocin, the main effective component of saffron, exerts protective effects against ischemia/reperfusion injury during strokes. However, the effects of crocin in myocardial ischemia/reperfusion injury, and the mechanisms involved, remain unknown. Pretreated with crocin for 7 days, C57BL/6N mice were subjected to 30 min of myocardial ischemia followed by 12[Formula: see text]h of reperfusion (for cardiac function and infarct size, cell apoptosis and necrosis). Neonatal mouse cardiomyocytes were subjected to 2 h of hypoxia followed by 4 h of reoxygenation. NMCM’s survival was assessed during hypoxia and reoxygenation in the presence or absence of the autophagy inhibitor 3-methyladenine or the inducer rapamycin. Western blotting was used to evaluate AMPK, Akt, and autophagy-related proteins. Autophagosome was observed using electron microscopy. In the in vivo experiment, crocin pretreatment significantly attenuated infarct size, myocardial apoptosis and necrosis, and improved left ventricular function following ischemia/reperfusion. In vitro data revealed that autophagy was induced during hypoxia, the levels of which were intensely elevated during reoxygenation. Crocin significantly promoted autophagy during ischemia, accompanied with the activation of AMPK. In contrast, crocin overtly inhibited autophagy during reperfusion, accompanied with Akt activation. Induction and inhibition of autophagy mitigated crocin induced protection against NMCMs injury during hypoxia and reoxygenation, respectively. Our data suggest that crocin demonstrated a myocardial protective effect via AMPK/mTOR and Akt/mTOR regulated autophagy against ischemia and reperfusion injury, respectively.

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Thu, Vu Thi, Ngo Thi Hai Yen, and Nguyen Thi Ha Ly. "Liquiritin from Radix Glycyrrhizae Protects Cardiac Mitochondria from Hypoxia/Reoxygenation Damage." Journal of Analytical Methods in Chemistry 2021 (August 6, 2021): 1–11. http://dx.doi.org/10.1155/2021/1857464.

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Aims. The purpose of this study was to evaluate the protective effect of liquiritin (LIQ) from Radix Glycyrrhizae on cardiac mitochondria against hypoxia/reoxygenation (HR) injury. Methods. H9C2 cells were subject to the HR model. LIQ purified from Radix Glycyrrhizae (purity > 95%) was administrated to reoxygenation period. Cell viability, mitochondrial mass, mitochondrial membrane potential, reactive oxygen species, and mitochondrial Ca2⁺ level were then assessed by using Cell Counting kit-8 and suitable fluorescence probe kits. Results. LIQ administration remarkably reduced the rate of HR damage via increasing H9C2 cell viability level and preserving mitochondria after HR. Particularly, 60 μM of LIQ posthypoxic treatment markedly reduced cell death in HR-subjected H9C2 cell groups ( p < 0.05 ). Interestingly, posthypoxic treatment of LIQ significantly prevented the loss of mitochondrial membrane potential, the decrease in mitochondrial mass, the increase in reactive oxygen species production, and the elevation of mitochondrial Ca2⁺ level in HR-treated H9C2 cells. Conclusion. The present study provides for the first time the cardioprotective of LIQ posthypoxic treatment via reducing H9C2 cell death and protecting cardiac mitochondria against HR damage.

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Shanmuganathan, Selvaraj, Derek J. Hausenloy, Michael R. Duchen, and Derek M. Yellon. "Mitochondrial permeability transition pore as a target for cardioprotection in the human heart." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H237—H242. http://dx.doi.org/10.1152/ajpheart.01192.2004.

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After an episode of myocardial ischemia, opening of the mitochondrial permeability transition pore (mPTP), at the onset of reperfusion, is a critical determinant of myocyte death. We investigated the role of the mPTP as a target for cardioprotection in the human heart. We subjected human atrial tissue, harvested from patients undergoing cardiac surgery, to a period of lethal hypoxia and investigated the effect of suppressing mPTP opening at the onset of reoxygenation. We found that suppressing mPTP opening at the onset of reoxygenation with known mPTP inhibitors cyclosporin A (CsA, 0.2 μmol/l) and sanglifehrin A (SfA, 1.0 μmol/l) 1) improved recovery of baseline contractile function from 29.4 ± 2.0% under control conditions to 48.7 ± 2.2% with CsA and 46.1 ± 2.3% with SfA ( P < 0.01) and 2) improved cell survival from 62.8 ± 5.3% under hypoxic control conditions to 91.4 ± 4.1% with CsA and 87.2 ± 6.2% with SfA ( P < 0.001). Furthermore, with a cell model in which oxidative stress was used to induce mPTP opening in human atrial myocytes, we demonstrated directly that CsA and SfA mediated their cardioprotective effects by inhibiting mPTP opening, as evidenced by an extension in the time required to induce mPTP opening from 116 ± 8 s under control conditions to 189 ± 10 s with CsA and 183 ± 12 s with SfA ( P < 0.01). We report that suppressing mPTP opening at the onset of reoxygenation protects human myocardium against lethal hypoxia-reoxygenation injury. This suggests that, in the human heart, the mPTP is a viable target for cardioprotection.

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Liu, Yanan, Mark Paterson, Shelley L. Baumgardt, Michael G. Irwin, Zhengyuan Xia, Zeljko J. Bosnjak, and Zhi-Dong Ge. "Vascular endothelial growth factor regulation of endothelial nitric oxide synthase phosphorylation is involved in isoflurane cardiac preconditioning." Cardiovascular Research 115, no. 1 (June 21, 2018): 168–78. http://dx.doi.org/10.1093/cvr/cvy157.

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Abstract Aims Previous studies indicate that nitric oxide derived from endothelial nitric oxide synthase (eNOS) serves as both trigger and mediator in anaesthetic cardiac preconditioning. The mechanisms underlying regulation of eNOS by volatile anaesthetics have not been fully understood. Therefore, this study examined the role of vascular endothelial growth factor (VEGF) in isoflurane cardiac preconditioning. Methods and results Wistar rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Isoflurane given prior to ischaemia/reperfusion significantly decreased myocardial infarct size from 60 ± 1% in control to 40 ± 3% (n = 8 rats/group, P < 0.05). The beneficial effects of isoflurane were blocked by neutralizing antibody against VEGF (nVEGF). Coronary arterial endothelial cells (ECs) alone or together with cardiomyocytes (CMs) were subjected to hypoxia/reoxygenation injury. The expression of VEGF and eNOS was analysed by western blot, and nitric oxide was measured by ozone-based chemiluminescence. In co-cultured CMs and ECs, isoflurane administered before hypoxia/reoxygenation attenuated lactate dehydrogenase activity and increased the ratio of phosphorylated eNOS/eNOS and nitric oxide production. The protective effect of isoflurane on CMs was compromised by nVEGF and after VEGF in ECs was inhibited with hypoxia inducible factor-1α short hairpin RNA (shRNA). The negative effect of hypoxia inducible factor-1α shRNA was restored by recombinant VEGF. Conclusion Isoflurane cardiac preconditioning is associated with VEGF regulation of phosphorylation of eNOS and nitric oxide production.

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Korge, Paavo, Peipei Ping, and James N. Weiss. "Reactive Oxygen Species Production in Energized Cardiac Mitochondria During Hypoxia/Reoxygenation." Circulation Research 103, no. 8 (October 10, 2008): 873–80. http://dx.doi.org/10.1161/circresaha.108.180869.

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Bordoni, Alessandra, Silvana Hrelia, Cristina Angeloni, Emanuele Giordano, Carlo Guarnieri, Claudio M. Caldarera, and Pier L. Biagi. "Green tea protection of hypoxia/reoxygenation injury in cultured cardiac cells." Journal of Nutritional Biochemistry 13, no. 2 (February 2002): 103–11. http://dx.doi.org/10.1016/s0955-2863(01)00203-0.

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DUAN, J., and M. KARMAZYN. "Comparative responses of interfibrillar and subsarcolemmal cardiac mitochondria to hypoxia/reoxygenation*." Journal of Molecular and Cellular Cardiology 18 (1986): 23. http://dx.doi.org/10.1016/s0022-2828(86)80098-0.

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KIRSHENBAUM, L., M. HILL, and P. SINGAL. "Endogenous antioxidants in isolated hypertrophied cardiac myocytes and hypoxia-reoxygenation injury." Journal of Molecular and Cellular Cardiology 27, no. 1 (January 1995): 263–72. http://dx.doi.org/10.1016/s0022-2828(08)80025-9.

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Lodovici, Maura, Piero Dolara, Sandra Amerini, Laura Mantelli, Fabrizio Ledda, Federico Bennardini, Marilena Fazi, Alessio Montereggi, and Germana Dini. "Effects of GM1 ganglioside on cardiac function following experimental hypoxia-reoxygenation." European Journal of Pharmacology 243, no. 3 (October 1993): 255–63. http://dx.doi.org/10.1016/0014-2999(93)90183-i.

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Hernandez, Olga M., Daryl J. Discher, Nanette H. Bishopric, and Keith A. Webster. "Rapid Activation of Neutral Sphingomyelinase by Hypoxia-Reoxygenation of Cardiac Myocytes." Circulation Research 86, no. 2 (February 4, 2000): 198–204. http://dx.doi.org/10.1161/01.res.86.2.198.

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Dong, Ying-Ying, Min Wu, Anthony P. C. Yim, and Guo-Wei He. "Effect of Hypoxia-Reoxygenation on Endothelial Function in Porcine Cardiac Microveins." Annals of Thoracic Surgery 81, no. 5 (May 2006): 1708–14. http://dx.doi.org/10.1016/j.athoracsur.2005.12.002.

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Seko, Yoshinori, Kazuyuki Tobe, Naoyuki Takahashi, Yasushi Kaburagi, Takashi Kadowaki, and Yoshio Yazaki. "Hypoxia and Hypoxia/Reoxygenation Activate Src Family Tyrosine Kinases and p21rasin Cultured Rat Cardiac Myocytes." Biochemical and Biophysical Research Communications 226, no. 2 (September 1996): 530–35. http://dx.doi.org/10.1006/bbrc.1996.1389.

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Zhou, Yanqiong, Ganggang Shi, Jinhong Zheng, Zhanqin Huang, Fenfei Gao, Yanmei Zhang, Fuxiao Guo, Qiangyong Jia, and Yanshan Zheng. "The protective effects of Egr-1 antisense oligodeoxyribonucleotide on cardiac microvascular endothelial injury induced by hypoxia–reoxygenationThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 88, no. 4 (August 2010): 687–95. http://dx.doi.org/10.1139/o10-021.

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Early growth response 1 (Egr-1) over-expression has been demonstrated in myocardial ischemia–reperfusion injury, which is closely associated with endothelial dysfunction. In the present study we investigated the expression of Egr-1 on cultured cardiac microvascular endothelial cells (CMECs) to help define the mechanism of myocardial ischemia–reperfusion injury. A model of cultured CMECs exposed to hypoxia–reoxygenation was developed in which synthesized Egr-1 sense and antisense oligodeoxyribonucleotide were transfected into the cells. The expression of Egr-1 was examined by Western blot analysis. Lactate dehydrogenase, malondialdehyde, superoxide dismutase, tumor necrosis factor α, and intercellular adhesion molecule 1 were measured after hypoxia–reoxygenation to assess cell function and injury. Cell morphology, cell viability, and neutrophil adhesion to the CMECs were measured to assess the degree of injury and inflammation. Only cells transfected with Egr-1 antisense oligodeoxyribonucleotide showed a significant reduction in Egr-1 protein expression following hypoxia–reoxygenation. Consistent with the down-regulation of Egr-1 expression, other forms of cell injury were significantly reduced in this group of cells, as evidenced by less alteration in cell morphology, a decrease in expression of tumor necrosis factor α and intercellular adhesion molecule 1, improved cell survival, and reduced neutrophil adhesion.

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Shah, A. M., H. S. Silverman, E. J. Griffiths, H. A. Spurgeon, and E. G. Lakatta. "cGMP prevents delayed relaxation at reoxygenation after brief hypoxia in isolated cardiac myocytes." American Journal of Physiology-Heart and Circulatory Physiology 268, no. 6 (June 1, 1995): H2396—H2204. http://dx.doi.org/10.1152/ajpheart.1995.268.6.h2396.

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Previous studies in isolated cardiac myocytes suggest that impaired relaxation during reoxygenation after brief hypoxia results from abnormal Ca(2+)-myofilament interaction. Recent studies indicate that guanosine 3',5'-cyclic monophosphate (cGMP)-elevating interventions selectively enhance myocardial relaxation. We investigated the effect of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) on posthypoxic relaxation in single rat myocytes, with simultaneous measurement of contraction and intracellular Ca2+ (indo 1 fluorescence). In control myocytes (n = 11), reoxygenation after 10 min of hypoxia markedly prolonged time to peak shortening (+36.5 +/- 4.2%) and half-relaxation time (+75.7 +/- 11.3% cf. normoxic values; both P < 0.001) and reduced diastolic length but did not change cytosolic Ca2+. Under normoxic conditions, 50 microM 8-BrcGMP slightly reduced time to peak shortening and half-relaxation time and increased diastolic length but did not alter cytosolic Ca2+. In the presence of 8-BrcGMP, there was no posthypoxic delay in twitch relaxation nor was there a decrease in diastolic length (half-relaxation time -5.8 +/- 3.3% cf. normoxic values; P < 0.05 cf. control group; n = 11). Cytosolic Ca2+ remained unaltered. Thus, 8-BrcGMP fully prevents impaired posthypoxic relaxation in isolated cardiac myocytes, probably by altering Ca(2+)-myofilament interaction.

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Robin, Elodie, Fabrice Marcillac, and Eric Raddatz. "A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 308, no. 7 (April 1, 2015): R614—R626. http://dx.doi.org/10.1152/ajpregu.00423.2014.

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To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5′-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation ± ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3β-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.

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Yamashita, N., M. Nishida, S. Hoshida, J. Igarashi, M. Hori, T. Kuzuya, and M. Tada. "Alpha 1-adrenergic stimulation induces cardiac tolerance to hypoxia via induction and activation of Mn-SOD." American Journal of Physiology-Heart and Circulatory Physiology 271, no. 4 (October 1, 1996): H1356—H1362. http://dx.doi.org/10.1152/ajpheart.1996.271.4.h1356.

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We examined whether or not alpha 1-adrenergic stimulation increases the tolerance of the heart to ischemia using a hypoxia-reoxygenation model of cardiac myocytes. After exposure to norepinephrine (NE; 0.2 microM) for 24 h, the manganese superoxide dismutase (Mn-SOD) content and activity in the cells were increased from 0.61 +/- 0.03 to 0.87 +/- 0.04 microgram/dish and 22 +/- 1 to 55 +/- 4 U/dish, respectively. The specific activity of Mn-SOD was also increased from 36 to 63 U/microgram Mn-SOD protein after the stimulation with NE. Prazosin (2 microM) abolished the increase in Mn-SOD activity (U/mg total protein). Creatine kinase (CK) release after hypoxia (PO2 7 mmHg; 3 h)-reoxygenation (1 h) from cells pretreated with NE in the presence of propranolol and yohimbine for 24 h was attenuated by 48% compared with that from cells without NE stimulation. When antisense oligodeoxyribonucleotides to Mn-SOD were added to myocyte cultures, the increase in Mn-SOD activity (U/mg total protein) and the attenuation of CK release after the addition of NE in the presence of propranolol and yohimbine were not observed. These results suggest that alpha 1-adrenergic stimulation increases the tolerance of myocytes to hypoxia through induction and activation of Mn-SOD.

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Stice, James P., Le Chen, Se-Chan Kim, J. S. Jung, A. L. Tran, T. T. Liu, and Anne A. Knowlton. "17β-Estradiol, Aging, Inflammation, and the Stress Response in the Female Heart." Endocrinology 152, no. 4 (February 8, 2011): 1589–98. http://dx.doi.org/10.1210/en.2010-0627.

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Abstract Heat shock proteins (HSPs) are a cardioprotective class of proteins induced by stress and regulated by the transcription factor, heat shock factor (HSF)-1. 17β-estradiol (E2) indirectly regulates HSP expression through rapid activation of nuclear factor-κB (NF-κB) and HSF-1 and protects against hypoxia. As males experience a loss of protective cellular responses in aging, we hypothesized that aged menopausal (old ovariectomized) rats would have an impaired HSP response, which could be prevented by immediate in vivo E2 replacement. After measuring cardiac function in vivo, cardiac myocytes were isolated from ovariectomized adult and old rats with and without 9 weeks of E2 replacement. Myocytes were treated with E2in vitro and analyzed for activation of NF-κB, HSF-1, and HSP expression. In addition, we measured inflammatory cytokine expression and susceptibility to hypoxia/reoxygenation injury. Cardiac contractility was reduced in old ovariectomized rats and could prevented by immediate E2 replacement in vivo. Subsequent investigations in isolated cardiac myocytes found that in vitro E2 activated NF-κB, HSF-1, and increased HSP 72 expression in adult but not old rats. In response to hypoxia/reoxygenation, myocytes from adult, but not old, rats had increased HSP 72 expression. In addition, expression of the inflammatory cytokines TNF-α and IL-1β, as well as oxidative stress, were increased in myocytes from old ovariectomized rats; only the change in cytokine expression could be attenuated by in vivo E2 replacement. This study demonstrates that while aging in female rats led to a loss of the cardioprotective HSP response, E2 retains its protective cellular properties.

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MacCormack, Tyson J., and William R. Driedzic. "Mitochondrial ATP-sensitive K+ channels influence force development and anoxic contractility in a flatfish, yellowtail flounderLimanda ferruginea, but not Atlantic codGadus morhuaheart." Journal of Experimental Biology 205, no. 10 (May 15, 2002): 1411–18. http://dx.doi.org/10.1242/jeb.205.10.1411.

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SUMMARYThe influence of ATP-sensitive K+ channels (KATPchannels) on cardiac performance during anoxia and reoxygenation was investigated in two species of fish showing different cardiac responses to anoxia. Force production in isometrically contracting ventricular muscle preparations from yellowtail flounder is potentiated at the onset of anoxia,while force immediately declines in Atlantic cod preparations. Glibenclamide,a general KATP blocker, impaired oxygenated force development in yellowtail flounder heart but was without effect on cod preparations. The mitochondrial KATP (mKATP)-specific blocker 5-hydroxydecanoic acid (5HD) improved oxygenated force production in yellowtail flounder heart without influencing contractility during anoxia or reoxygenation. The specific mKATP agonist diazoxide preserved resting tension and eliminated anoxic force potentiation in yellowtail flounder heart preparations. Neither 5HD nor diazoxide affected contractility in cod ventricle preparations. Results indicate that KATP channels can modulate contractility in yellowtail flounder heart and are potentially important in cardiac hypoxia survival in this species.

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Journal articles on the topic 'Cardiac hypoxia reoxygenation'

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