Sarcolemmal integrity and metabolic competence of cardiomyocytes under anoxia-reoxygenation

Siegmund, B.; Koop, Anja; Klietz, T.; Schwartz, Peter J.; Piper, Hans Michael

doi:10.1152/ajpheart.1990.258.2.h285

Cited by 62 publications

(39 citation statements)

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“…The pathogenic relationship between ATP loss and cell necrosis has long been a matter of controversy (Andreoli, 1989). Our results correlate well with the finding of Siegmund et al (1990) that ATP-depleted anoxic cardiomyocytes did not necessarily leak LDH. In contrast, other investigators have concluded that maintenance of cardiomyocyte ATP content is a prerequisite for sarcolemmal integrity (Higgins and Bailey, 1983;Murphy et al, 1987).…”

Section: -supporting

confidence: 89%

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Janero¹,

Hreniuk²,

Sharif³

1991

Journal Cellular Physiology

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Oxidative stress induced by hydrogen peroxide (H2O2) may contribute to the pathogenesis of ischemic-reperfusion injury in the heart. For the purpose of investigating directly the injury potential of H2O2 on heart muscle, a cellular model of H2O2-induced myocardial oxidative stress was developed. This model employed primary monolayer cultures of intact, beating neonatal-rat cardiomyocytes and discrete concentrations of reagent H2O2 in defined, supplement-free culture medium. Cardiomyocytes challenged with H2O2 readily metabolized it such that the culture content of H2O2 diminished over time, but was not depleted. The consequent H2O2-induced oxidative stress caused lethal sarcolemmal disruption (as measured by lactate dehydrogenase release), and cardiomyocyte integrity could be preserved by catalase. During oxidative stress, a spectrum of cellular derangements developed, including membrane phospholipid peroxidation, thiol oxidation, consumption of the major chain-breaking membrane antiperoxidant (alpha-tocopherol), and ATP loss. No net change in the protein or phospholipid contents of cardiomyocyte membranes accompanied H2O2-induced oxidative stress, but an increased turnover of these membrane constituents occurred in response to H2O2. Development of lethal cardiomyocyte injury during H2O2-induced oxidative stress did not require the presence of H2O2 itself; a brief "pulse" exposure of the cardiomyocytes to H2O2 was sufficient to incite the pathogenic mechanism leading to cell disruption. Cardiomyocyte disruption was dependent upon an intracellular source of redox-active iron and the iron-dependent transformation of internalized H2O2 into products (e.g., the hydroxyl radical) capable of initiating lipid peroxidation, since iron chelators and hydroxyl-radical scavengers were cytoprotective. The accelerated turnover of cardiomyocyte-membrane protein and phospholipid was inhibited by antiperoxidants, suggesting that the turnover reflected molecular repair of oxidized membrane constitutents. Likewise, the consumption of alpha-tocopherol and the oxidation of cellular thiols appeared to be epiphenomena of peroxidation. Antiperoxidant interventions coordinately abolished both H2O2-induced lipid peroxidation and sarcolemmal disruption, demonstrating that an intimate pathogenic relationship exists between sarcolemmal peroxidation and lethal compromise of cardiomyocyte integrity in response to H2O2-induced oxidative stress. Although sarcolemmal peroxidation was causally related to cardiomyocyte disruption during H2O2-induced oxidative stress, a nonperoxidative route of H2O2 cytotoxicity was also identified, which was expressed in the complete absence of cardiomyocyte-membrane peroxidation. The latter mode of H2O2-induced cardiomyocyte injury involved ATP loss such that membrane peroxidation and cardiomyocyte disruption on the one hand and cellular de-energization on the other could be completely dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: -supporting

confidence: 89%

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Janero¹,

Hreniuk²,

Sharif³

1991

Journal Cellular Physiology

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“…[12][13][14][15] Na ϩ /K ϩ -ATPase activity is highly dependent on myocardial energy, but previous studies have shown that an inadequate energy recovery cannot satisfactorily explain this impairment in cardiomyocytes showing ATP-dependent hypercontracture. 16,17 The mechanisms of this Na ϩ /K ϩ -ATPase failure during reperfusion and contribution to Ca 2ϩ overload and cell death have not been completely elucidated. Na ϩ /K ϩ -ATPase is a transmembrane heterodimer protein composed of ␣ and ␤ subunits.…”

Section: Abstract-namentioning

confidence: 99%

Calpain-Mediated Impairment of Na ⁺ /K ⁺ –ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia

Inserte

Garcı́a-Dorado

Hernando

et al. 2005

Circulation Research

115

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Na + overload and secondary Ca 2+ influx via Na + /Ca 2+ exchanger are key mechanisms in cardiomyocyte contracture and necrosis during reperfusion. Impaired Na + /K + –ATPase activity contributes to Na + overload, but the mechanism has not been established. Because Na + /K + –ATPase is connected to the cytoskeleton protein fodrin through ankyrin, which are substrates of calpains, we tested the hypothesis that calpain mediates Na + /K + –ATPase impairment in reperfused cardiomyocytes. In isolated rat hearts reperfused for 5 minutes after 60 minutes of ischemia, Na + /K + –ATPase activity was reduced by 80%, in parallel with loss of α-fodrin and ankyrin-B and detachment of α 1 and α 2 subunits of Na + /K + –ATPase from the membrane–cytoskeleton complex. Calpain inhibition with MDL-7943 during reperfusion prevented the loss of these proteins, increased Na + /K + –ATPase activity, attenuated lactate dehydrogenase release, and improved contractile recovery, and these beneficial effects of MDL-7943 were reverted by ouabain. The impairment of Na + /K + –ATPase was not a mere consequence of cell death because it was not altered in hearts in which contracture and cell death had been prevented by contractile blockade with 2,3-butanedione monoxime. In these hearts, concomitant calpain inhibition preserved Na + /K + –ATPase content and function and attenuated cell death occurring on withdrawal of 2,3-butanedione monoxime. In vitro assay showed no detectable degradation of Na + /K + –ATPase subunits after 10 minutes of incubation with activated calpain. Thus, we conclude that calpain activation contributes to the impairment of Na + /K + –ATPase during early reperfusion and that this effect is mainly mediated by degradation of the anchorage of Na + /K + –ATPase to the membrane cytoskeleton.

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“…In this buffer the osmolality was reduced to 80 mosmol kg¢ to mimic the magnitude of the trans-sarcolemmal osmotic gradient present during the in situ reperfusion (TranumJensen et al 1987). Previous studies have shown that in the presence of this osmotic stress, hypercontracture induced by reoxygenation results in sarcolemmal rupture (Ruiz-Meana et al 1995, while in its absence most hypercontracted cardiomyocytes retain their sarcolemmal integrity despite hypercontracture (Siegmund et al 1990). Loss of cell integrity was characterized by quantification of lactate dehydrogenase (LDH) leakage from the cells into the incubation medium.…”

Section: Myocyte Isolationmentioning

confidence: 99%

Protective Effect of HOE642, a Selective Blocker of Na⁺‐H⁺ Exchange, Against the Development of Rigor Contracture in Rat Ventricular Myocytes

Ruiz‐Meana

Garcı́a-Dorado

Julià

et al. 2000

Experimental Physiology

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The objective of this study was to investigate the effect of Na+‐H+ exchange (NHE) and HCO3−‐Na+ symport inhibition on the development of rigor contracture. Freshly isolated adult rat cardiomyocytes were subjected to 60 min metabolic inhibition (MI) and 5 min re‐energization (Rx). The effects of perfusion of HCO3− or HCO3−‐free buffer with or without the NHE inhibitor HOE642 (7 μM) were investigated during MI and Rx. In HCO3−‐free conditions, HOE642 reduced the percentage of cells developing rigor during MI from 79 ± 1% to 40 ± 4% (P < 0.001) without modifying the time at which rigor appeared. This resulted in a 30% reduction of hypercontracture during Rx (P < 0.01). The presence of HCO3− abolished the protective effect of HOE642 against rigor. Cells that had developed rigor underwent hypercontracture during Rx independently of treatment allocation. Ratiofluorescence measurement demonstrated that the rise in cytosolic Ca2+ (fura‐2) occurred only after the onset of rigor, and was not influenced by HOE642. NHE inhibition did not modify Na+ rise (SBFI) during MI, but exaggerated the initial fall of intracellular pH (BCEFC). In conclusion, HOE642 has a protective effect against rigor during energy deprivation, but only when HCO3−‐dependent transporters are inhibited. This effect is independent of changes in cytosolic Na+ or Ca2+ concentrations.

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Sarcolemmal integrity and metabolic competence of cardiomyocytes under anoxia-reoxygenation

Cited by 62 publications

References 0 publications

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Calpain-Mediated Impairment of Na ⁺ /K ⁺ –ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia

Protective Effect of HOE642, a Selective Blocker of Na⁺‐H⁺ Exchange, Against the Development of Rigor Contracture in Rat Ventricular Myocytes

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Sarcolemmal integrity and metabolic competence of cardiomyocytes under anoxia-reoxygenation

Cited by 62 publications

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Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Hydrogen peroxide‐induced oxidative stress to the mammalian heart‐muscle cell (cardiomyocyte): Lethal peroxidative membrane injury

Calpain-Mediated Impairment of Na + /K + –ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia

Protective Effect of HOE642, a Selective Blocker of Na+‐H+ Exchange, Against the Development of Rigor Contracture in Rat Ventricular Myocytes

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Calpain-Mediated Impairment of Na ⁺ /K ⁺ –ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia

Protective Effect of HOE642, a Selective Blocker of Na⁺‐H⁺ Exchange, Against the Development of Rigor Contracture in Rat Ventricular Myocytes