p53 Induces Myocyte Apoptosis via the Activation of the Renin–Angiotensin System
Abstract
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.
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Several proapoptotic BCL-2 family members, including BAX, BBC3 (PUMA) and PMAIP1 (NOXA), are activated by p53.
“Several proapoptotic BCL-2 family members, including BAX,41, 42, 43 BBC3 (PUMA)181 and PMAIP1 (NOXA),182 are activated by p53.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [42]
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- Authors
- Pierzchalski, P., Reiss, K., Cheng, W., Cirielli, C., Kajstura, J., Nitahara, J. A., Rizk, M., Capogrossi, M. C., & Anversa, P.
- Affiliations
- New York Medical College (US)
- National Institute on Aging (US)
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 1997-07
- Volume
- 234
- Issue
- 1
- Pages
- 57-65
- ISSN
- 0014-4827 (ISSN-L)
- OpenAlex
- W2050848660
- Cited by
- 135
- References
- 28
- Citations by year
- 2026: 1 · 2023: 3 · 2020: 2 · 2019: 4 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 3 · 2012: 1
- FWCI
- 14.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl040561-07)
- National Heart, Lung, and Blood Institute (R01HL039902, HL39902, HL 38132, HL-40561, R01HL038132)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p53, apoptosis, renin-angiotensin system, angiotensin II, ventricular myocytes, Bcl-2, Bax, angiotensinogen, angiotensin II type 1 receptor, losartan, myocardial function
- MeSH terms
- Adenoviridae, Angiotensin II, Angiotensinogen, Animals, Heart Ventricles, Humans, Molecular Sequence Data, Myocardium, Promoter Regions, Genetic, Proto-Oncogene Proteins, Receptors, Angiotensin, Renin, RNA, Messenger, Gene Expression, Tumor Suppressor Protein p53, Rats, Sprague-Dawley, Apoptosis, Gene Transfer Techniques, Muscle Fibers, Skeletal, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Rats
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