A mechanistic role for cardiac myocyte apoptosis in heart failure

Abstract

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80–250 myocytes per 105 nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 105 nuclei, compared with 1.5 myocytes per 105 nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

“…A similar PUMAdependency of cardiomyocyte apoptosis has been found in ischemia-reperfusion model of cultured cardiomyocyte [36]. This pathway would also involve BCL2-protein interaction [37,38], BAX/BAK-induced MOMP [39] and activation of initiator and activator caspases [24,39,40] similar to the above presented canonical intrinsic apoptosis in cancer cells. Likewise, invocation of the extrinsic apoptosis program by DOX via FAS-L or TRAIL ligands has also been detected in cardiomyocytes similar to cancer cells [41,42], potentially attaining robust caspase-3 activation by invoking MOMP (type II cells, Fig 1).…”

“…Moreover, in a transgenic mouse model with constitutively active caspase-8 only a small detectable elevation of apoptosis only 23 myocytes per 10 5 cells sufficed to induce a dilated cardiomyopathy phenotype [24]. Importantly, this amount is four-to tenfold lower than that measured in three independent studies of failing human hearts.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…Endoplasmic reticulum stress and heart failure Various stimuli, such as hypoxia [132,133] , Ang II stimulation [134] , oxidative stress [135] and inflammatory factors [136] , have been proposed to trigger ERS during heart failure (HF). However, the role of ERS in heart failure is still in dispute.…”

Development of an inducible suicide gene system based on human caspase 8

“…Using this method with a former version of homodimerization-regulated caspase, Wencker et al have recently demonstrated that myocyte apoptosis can be a causal mechanism of heart failure. 53 Mouse models for different human disorders in which apoptosis is involved could also be generated using such a strategy. For example, Mallet et al 54 recently used a similar approach with caspase 3 specifically expressed in the liver of transgenic mice.…”