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 bax, cannot trigger apoptosis. However, p53 may enhance not only transcription of bax and repress bcl-2, but also may upregulate the local renin-angiotensin system, inducing the formation and secretion of angiotensin II from the cells. To test this hypothesis, adult rat ventricular myocytes were infected with AdCMV.p53, which resulted in downregulation of Bcl-2, upregulation of Bax, and death of 34% of the cells. Gel retardation assays demonstrated p53 binding in the promoters of angiotensinogen and angiotensin II AT1 receptor subtype. Angiotensinogen and AT1 mRNAs increased in AdCMV.p53 cells and this phenomenon was associated with a 14-fold increase in the secretion of angiotensin II. The AT1 receptor blocker losartan and angiotensin 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 pathway in p53-mediated apoptosis may be critical in the alterations of myocardial function in the pathologic heart.
Pierzchalski
P
P
Department of Medicine, New York Medical College, Valhalla 10595, USA.
Reiss
K
K
Cheng
W
W
Cirielli
C
C
Kajstura
J
J
Nitahara
J A
JA
Rizk
M
M
Capogrossi
M C
MC
Anversa
P
P
D000256:Adenoviridae; D000804:Angiotensin II / Q000502:physiology*; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology; D006801:Humans; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin