Myocyte cell death in the diseased heart.

Abstract

In this issue of Circulation Research , Karwatowska-Prokopczuk et al1 and Takemura et al2 report, respectively, that inhibition of the vacuolar proton ATPase (VPATPase) enhances apoptosis in neonatal cardiac myocytes during metabolic recovery and that the progression of the healing process after infarction involves apoptotic death of inflammatory and interstitial cells. We will discuss these 2 studies separately, because the first addresses important mechanisms of myocyte death and survival, and the second provides new information on scarring of the postinfarcted heart. Both studies emphasize directly or indirectly through in vitro1 and in vivo2 experiments the role of apoptosis in ischemic injury. Two different phases of cardiac damage are examined: myocyte death and reparative fibrosis. In the first article,1 the recognition that alkalinization of myocytes is regulated not only by activation of the Na+-H+ antiport and the Na+-HCO3− symport but also via a third proton-extruding system, VPATPase,1,3 may elucidate some of the critical events affecting the ischemic myocardium. Whether myocardial ischemia occurs in vivo in the absence4,5 or presence5,6 of reperfusion, cell death by apoptosis is the predominant pathological consequence; its etiology, however, remains to be defined. Similarly, the paradoxical beneficial impact of Na+-H+ exchange inhibition during ischemia1 is unclear. The documentation that the ATP-dependent vacuolar proton pump may play a role in hypoxia-induced myocyte apoptosis is significant because it points to alterations in pHi as critical for the transmission of a death signal to myocytes in vivo. Impairment of VPATPase affects the extrusion of protons from the cytoplasm to intracellular acidic complexes, decreasing pHi, and abolishes the protective influence of attenuation of the Na+-H+ exchanger on Ca2+ overload.1 The observations by Karwatowska-Prokopczuk et …