Inhibition of p53 function prevents renin-angiotensin system activation and stretch-mediated myocyte apoptosis

To determine whether stretch-induced activation of p53 is necessary for the up-regulation of the local renin-angiotensin system and angiotensin II (An g II)-induced apoptosis, ventricular myocytes were infected with an adenovi ral vector carrying mutated p53, Adp53m, before 12 hours of stretch. Noninf ected myocytes and myocytes infected with AdLacZ served as controls. Stretc hing of Adp53m-infected myocytes prevented stimulation of p53 function that conditioned the expression of p53-dependent genes; quantity of angiotensin ogen (Aogen), AT(1), and Bar decreased, whereas Bcl-2 increased. Ang II gen eration was not enhanced by stretch. Conversely, stretch produced opposite changes in noninfected and AdLacZ-infected myocytes: Aogen increased twofol d, AT(1) increased 2.1-fold, Bar increased 2.5-fold, and Ang II increased 2 .4-fold. These responses were coupled with 4.5-fold up-regulation of wild-t ype p53. Stretch elicited comparable adaptations in p53-independent genes, in the presence or absence of mutated p53; renin increased threefold, angio tensin-converting enzyme increased ninefold, and AT(2) increased 1.7-fold, Infection with Adp53m inhibited myocyte apoptosis after stretch. Conversely , stretch increased apoptosis by 6.2-fold in myocytes with elevated endogen ous wild-type p53, Thus, a competitor of p53 function interfered with both stretch-induced Ang II formation and apoptosis, indicating that p53 is a ma jor modulator of myocyte renin-angiotensin system and cell survival after m echanical deformation.