Key result
Poly-ADP-ribose polymerase inhibition blocked AIF release and improved cell viability in hypertrophied cardiomyocytes (74%), whereas caspase inhibition provided no significant protection (23%).
Absolute Event Rate: 74% vs 63%
A caspase-independent, AIF-mediated pathway plays a critical role in apoptosis of hypertrophic cardiomyocytes, unlike in non-hypertrophic cells where caspase-dependent pathways dominate.
Suggests PARP inhibition as potential strategy in cardiac hypertrophy; leaves open whether AIF-mediated protection translates to human disease.
AIMS: The caspases are thought to be central mediators of the apoptotic program, but recent data indicate that apoptosis may also be mediated by caspase-independent mechanisms such as apoptosis-inducing factor (AIF). The role of AIF-induced apoptosis in heart, however, is currently not well understood. The aim of this study was to investigate the presence of and conditions for AIF-induced cardiac apoptosis in vitro. METHODS AND RESULTS: Hypertrophic cardiomyocyte (H-CM) cultures were prepared from the hearts of Dahl salt-sensitive rats fed a high salt diet. Apoptotic stimulation induced by hypoxia/reoxygenation or staurosporine (1 microM) enhanced AIF release in H-CMs compared with non-hypertrophic cardiomyocytes (N-CMs). Caspase inhibition using zVAD.fmk (25 microM) or overexpression of CrmA using recombinant adenovirus only partially protected N-CMs from apoptosis (63 +/- 0.93%) and provided no significant protection against apoptosis in hypertrophic cells (23 +/- 1.03%). On the other hand, poly-ADP-ribose polymerase inhibition using 4-AN (20 microM) during apoptotic stimulation blocked the release of AIF from mitochondria and significantly improved cell viability in hypertrophied cardiomyocytes (74 +/- 1.18%). CONCLUSION: A caspase-dependent, apoptotic pathway is important for N-CM death, whereas a caspase-independent, AIF-mediated pathway plays a critical role in H-CMs.
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Choudhury et al. (2009) studied Cardiac apoptosis in hypertrophic cardiomyocytes. Poly-ADP-ribose polymerase inhibition (4-AN) vs Caspase inhibition (zVAD.fmk or CrmA) vs. Non-hypertrophic cardiomyocytes was evaluated on Cell viability / protection from apoptosis. Poly-ADP-ribose polymerase inhibition blocked AIF release and improved cell viability in hypertrophied cardiomyocytes (74%), whereas caspase inhibition provided no significant protection (23%).
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