Gelsolin and Cardiac Myocyte Apoptosis

Abstract

See related article, pages 896–904 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 β1-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 Figure. Gelsolin and cell death pathways in cardiac myocytes. Gelsolin can translocate to the nucleus and elevate DNase I through the gelsolin/HIF-1α/DNase I pathway, in part, in a caspase-independent manner. Caspase-3 can cleave gelsolin between residues Asp352 and Gly353. The N-terminal gelsolin fragment has a proapoptotic function. Gelsolin may relate to the downregulation of survival factors in myocytic apoptosis post-MI through the caspase cleavage of PARP, reduction of Akt activation, and decrease of Bcl-2 expression. Caspase-dependent pathways activate …