Possible Therapeutic Targets in Cardiac Myocyte Apoptosis

Abstract

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.

TNF-α- Mediated-p38-Dependent Signaling Pathway Contributes to Myocyte Apoptosis in Rats Subjected to Surgical Trauma

“…In the present study, our results showed that TNF-α activated p38 pathway, and the subsequent activation of p38 mediated myocyte apoptosis. It was consistent with previous report that myocyte susceptibility to apoptosis was potentiated when p38 activation was prolonged by tyrosine phosphatase inhibition [35]. …”

“…Aboved reports further supported our results that p38 pathway played the important role in the induction of apoptosis. Besides pro-apoptotic function, anti-apoptotic action has been ascribed to p38 [35]. Whether p38 acts as a cytoprotective or pro-apoptotic agent likely depends on both the intensity and duration of p38 activation.…”

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: The role of JNK signaling

“…It has been well established that cardiomyocyte cell death during I/R injury can be induced both by apoptosis and necrosis [40]. FGF2 and JNK are both involved in regulating apoptosis [9,41,42].…”

Apoptosis and Autophagy: Decoding Calcium Signals that Mediate Life or Death

“…Much like glucocorticoids, treatment with higher concentrations of angiotensin II results in apoptosis that can be blocked by receptor antagonists (Andreka et al 2004). As depicted in Figure 2, stimulation of cardiomyocytes with angiotensin II causes an acute release of cytosolic calcium, and several reports suggest that calcium elevation contributes to apoptosis .…”