Gene 33 is a potential inducer of cardiomyocyte apoptosis

Abstract

Apoptosis has been implicated in the cardiomyopathy associated with acute and chronic heart failure. Myocardial infarction, cardiac hypertrophy and especially ischemia/reperfusion have been shown to lead to cardiomyocyte apoptosis. Despite previous findings, the role of apoptosis in cardiomyopathy and the mechanism of apoptosis in cardiomyocytes are poorly understood. Gene 33 encodes a 50 kD polypeptide that in numerous tissues is inducible by a wide variety of stimuli. Although Gene 33′s molecular structure suggests it functions as an adaptor/scaffold protein, very little is known about the biological functions of Gene33. It has been shown that Gene 33 binds to EGF receptor family receptor tyrosine kinases and suppresses their downstream signaling. Gene 33, when over expressed, also binds GTP-bound Cdc42 and activates JNK. We find that Gene 33 inhibits EGFR tyrosine phosphorylation thus accounting for the mechanism by which Gene 33 suppresses EGF effectors such as ERK and Akt, as well as EGF-stimulated protein synthesis and DNA synthesis. Here we show that infection of neonatal rat cardiomyocytes with a recombinant adenovirus expressing Gene 33 is potently apoptogenic. Consistent with this, ectopic expression of Gene 33 results in activation of cardiomyocyte caspase 3. Western blot analysis reveals elevated levels of Gene 33 protein in a mouse model for myocardial infarction. Of note, both Western blot and immunohistochemistry indicate that expression of the Gene 33 polypeptide is higher in the infarct region compared to the none-infarct zone. These results strongly suggest a role of Gene 33 in cardiomyocyte apoptosis. We therefore propose a model in which Gene 33 is induced by stress conditions such as myocardial infarction, ischemia/reperfusion and possibly late-stage cardiac hypertrophy. Gene 33 then participates in triggering pathophysiologic cardiomyocyte apoptosis.