Myocyte Apoptosis During Acute Myocardial Infarction in the Mouse Localizes to Hypoxic Regions but Occurs Independently of p53

Significant numbers of myocytes die by apoptosis during myocardial infarction. The molecular mechanism of this process, however, remains largely unexplored. To facilitate a molecular genetic analysis, we have developed a model of ischemia-induced cardiac myocyte apoptosis in the mouse. Surgical occlusion of the left coronary artery results in apop-tosis, as indicated by the presence of nucleosome ladders and in situ DNA strand breaks. Apoptosis occurs mainly in cardiac myocytes, and is shown for the first time to be lim-ited to hypoxic regions during acute infarction. Since hy-poxia-induced apoptosis in other cell types is dependent on p53, and p53 is induced by hypoxia in cardiac myocytes, we investigated the necessity of p53 for myocyte apoptosis dur-ing myocardial infarction. Myocyte apoptosis occurs as readily, however, in the hearts of mice nullizygous for p53 as in wild-type littermates. These data demonstrate the ex-istence of a p53-independent pathway that mediates myo-cyte apoptosis during myocardial infarction. ( J. Clin. In-vest