P53 INDUCES MYOCYTE APOPTOSIS VIA THE ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM

The mechanism by which p53 activates apoptosis in various cell systems is unknown. In the absence of an external death stimulus, p53 and p53 -dependent genes, bcl-2 and bar, cannot trigger apoptosis. However, p5 3 may enhance not only transcription of bar and repress bcl-2, but als o may upregulate the local renin-angiotensin system, inducing the form ation and secretion of angiotensin II from the cells. To test this hyp othesis, adult rat ventricular myocytes were infected with AdCMV.p53, which resulted in downregulation of Bcl-2, upregulation of Bar, and de ath of 34% of the cells. Gel retardation assays demonstrated p53 bindi ng in the promoters of angiotensinogen and angiotensin II AT, receptor subtype. Angiotensinogen and ATI mRNAs increased in AdCMV.p53 cells a nd this phenomenon was associated with a 14-fold increase in the secre tion of angiotensin II. The AT(1) receptor blocker losartan and angiot ensin II antibody prevented p53-induced apoptosis. Thus, p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2/Bax ratio in the cells, triggering apoptosis. The identification of this new pa thway in p53-mediated apoptosis may be critical in the alterations of myocardial function in the pathologic heart. (C) 1997 Academic Press.