Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways

Abstract

A sequence of intermittent interruptions of oxygen supply (i.e., postconditioning, Postcon) at reoxygenation reduces oxidant-induced cardiomyocyte loss. This study tested the hypothesis that prevention of cardiomyocyte apoptosis by Postcon is mediated by mitogen-activated protein kinases pathways. Primary cultured neonatal rat cardiomyocytes were exposed to 3 h hypoxia followed by 6 h of reoxygenation. Cardiomyocytes were postconditioned by three cycles each of 5 min reoxygenation and 5 min hypoxia after prolonged hypoxia. Relative to hypoxia alone, reoxygenation stimulated expression of JNKs and p38 kinases, corresponding to increased activity of JNKs (phospho-c-Jun) and p38 (phospho-ATF2). The level of TNFalpha in cell lysates, activity of cytosolic caspases-8, -3, expression of Bax and the number of apoptotic cardiomyocytes were increased while expression of Bcl-2 was decreased with reoxygenation. Consistent with an attenuation in generation of superoxide anions detected by lucigenin-enhanced chemiluminescence at early period of reoxygenation, treatment of cardiomyocytes with Postcon further reduced expression and activity of JNKs and p38 kinases, level of TNFalpha, the frequency of apoptotic cells and expression of Bax. However, the inhibitory effects of Postcon on these changes were lost when its application was delayed by 5 min after the start of reoxygenation. Addition of a JNK/p38 stimulator, anisomycin into cardiomyocytes at the beginning of reoxygenation eliminated protection by Postcon. These data suggest that 1) hypoxia/reoxygenation elicits cardiomyocyte apoptosis in conjunction with expression and activation of JNK and p38 kinases, release of TNFalpha, activation of caspases, and an increase in imbalance of pro-/anti-apoptotic proteins; 2) Postcon attenuates cardiomyocyte apoptosis, potentially mediated by inhibiting JNKs/p-38 signaling pathways and reducing TNFalpha release and caspase expression.

Post-conditioning with gradually increased reperfusion provides better cardioprotection in rats

“…Myocardial ischemia/reperfusion has been shown to activate p38/ JNK MAPK, resulting in cardiac injury and cell death, most prominently via apoptosis. In their study using neonatal rat cardiocytes, Sun et al [20] found that hypoxic post-conditioning could inhibit the expression of p38/ JNK MAPK, which reduced the expression of TNF-α and Bax, and conversely that anisomycin, an activator of p38/JNK MAPK, could offset this protection. The level of phosphorylation of p38/JNK was lower in the GIR group than in the R/I, ER and GDR groups.…”

Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis

“…Apoptosis is important in cardiovascular disease and may contribute to the development and progression of cardiac dysfunction and heart failure (8)(9)(10). In vitro and in vivo studies have suggested a number of potential mechanisms of these adverse effects, including the theory that aldosterone induces apoptosis in myocytes via activation of the calcineurin, p38 MAPK, JNK and ERK1/2 pathways.…”

“…Additionally, previous studies provide evidence that aldosterone-mediated myocyte apoptosis is an important component of cardiovascular diseases (9,10). Several mechanisms which may link aldosterone and apoptosis have been suggested, including the activation of the membrane receptor-mediated calcineurin-Bad, c-Jun N-terminal kinase (JNK) and ERK1/2 pathways (11)(12)(13).…”

Effects of Limb Remote Postconditioning on Apoptosis and Long-Term Neurological Outcomes of Focal Cerebral Ischemia/Reperfusion Injury in Rats

“…Recent developments in cardiac physiology have indicated that PostC significantly reduces infarct size and inhibits inflammation and apoptosis [17][18][19][20][21]. Zhao [22] at first documented that PostC reduced infarct size in cerebral I/R injury.…”

“…Recently, the protective effect of RPostC against focal cerebral ischemia in rats was also verified [16]. However, its potential protective mechanisms have not been established.Recent developments in cardiac physiology have indicated that PostC significantly reduces infarct size and inhibits inflammation and apoptosis [17][18][19][20][21]. Zhao [22] at first documented that PostC reduced infarct size in cerebral I/R injury.…”