Gelsolin and cardiac myocyte apoptosis: a new target in the treatment of postinfarction remodeling.

Cardiac remodeling is among the most important problems in patients with heart failure.1,2 Ventricular remodeling involves numerous processes, involving molecular alterations, myocardial changes, and the abnormal geometry of the chamber. As a consequence of myocardial infarction (MI), ventricular remodeling occurs immediately as an adaptive response to maintain cardiac output.3 However, ventricular function and prognosis deteriorate with ongoing remodeling. MI triggers an inflammatory response, including cytokine activation, a cascade of intracellular signaling, and neurohormonal activation4,5 These processes result in scar formation and myocyte loss through necrosis, apoptosis, and autophagy.6 An MI has been shown to be a prominent inducer of cardiomyocyte apoptosis, which, in turn, may contribute to progressive postinfarction remodeling, as demonstrated by recently reported animal and human studies.7 Yet, the pathophysiological mechanisms of apoptosis in cardiac myocytes remain unclear. The elucidation of the mechanisms of cardiomyocyte apoptosis may lead to an improved understanding of postinfarction remodeling and thereby possibly improve patient care. Cardiomyocytic apoptosis post-MI is induced by angiotensin II and 1-adrenergic stimulation, reactive oxygen species, overstretch, and nitric oxide.8 Apoptotic programmed cell death is characterized by DNA fragmentation attributable to the activation of an endogenous endonuclease. This endonuclease-mediated breakdown of DNA in apoptosis is activated through “caspase-dependent” pathways or “caspase-independent” pathways (Figure).9 Caspase-dependent pathways in apoptosis have 3 major cascades. One, the endoplasmic reticulum stress induced by extracellular or intracellular death signals activates caspase12. Two, the mitochondrial stress induced by death signals stimulates the release of cytochrome c, resulting in the activation of caspase-9. Three, the death ligand binding induces death receptors to recruit FADD (Fas-associated death domain) and/or TRADD (tumor necrosis factor receptor-I–associated death domain), and caspase-8 is activated. These 3 cascades induce caspase-3 activation, leading to the cleavage of downstream targets of caspase-3, including the ICAD (inhibitor of CAD [caspase-3–activated DNase]) and PARP (poly[ADP-ribose] polymerase). Finally, endonuclease is activated, which induces DNA fragmentation. Caspase-independent pathways include the p38 mitogenactivated protein kinase signaling cascade and apoptosisinducing factor.10 Apoptosis is also regulated by a number of factors. Bax and Bid stimulate apoptogenic release, whereas activation of the pathway is prevented by the antiapoptotic proteins, including Bcl-2 and Akt.