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.