Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase

Abstract

MDM2 is an E3 ubiquitin ligase that regulates the proteasomal degradation and activity of proteins involved in cell growth and apoptosis, including the tumor suppressors p53 and retinoblastoma and the transcription factor E2F1. Although the effect of several MDM2 targets on cardiomyocyte survival and hypertrophy has already been investigated, the role of MDM2 in these processes has not yet been established. We have, therefore, analyzed the effect of overexpression as well as inhibition of MDM2 on cardiac ischemia/reperfusion injury and hypertrophy. Here we show that isolated cardiac myocytes overexpressing MDM2 acquired resistance to hypoxia/reoxygenation-induced cell death. Conversely, inactivation of MDM2 by a peptide inhibitor resulted in elevated p53 levels and promoted hypoxia/reoxygenation-induced apoptosis. Consistent with this, decreased expression of MDM2 in a genetic mouse model was accompanied by reduced functional recovery of the left ventricles determined with the Langendorff ex vivo model of ischemia/reperfusion. In contrast to cell survival, cell hypertrophy induced by the alpha-agonists phenylephrine or endothelin-1 was inhibited by MDM2 overexpression. Collectively, our studies indicate that MDM2 promotes survival and attenuates hypertrophy of cardiac myocytes. This differential regulation of cell growth and cell survival is unique, because most other survival factors are prohypertrophic. MDM2, therefore, might be a potential therapeutic target to down-regulate both cell death and pathologic hypertrophy during remodeling upon cardiac infarction. In addition, our data also suggest that cancer treatments with MDM2 inhibitors to reactivate p53 may have adverse cardiac side effects by promoting cardiomyocyte death.