Document Detail

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy.
MedLine Citation:
PMID:  16632544     Owner:  NLM     Status:  MEDLINE    
Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP(+/+)) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP(+/+) but not in PARP(-/-) mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP(-/-) cardiomyocytes, angiotensin II (1 microM) treatment significantly increased protein synthesis in PARP(+/+) myocytes, as measured by (3)H-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10-20 microM), robust myocyte cell death was observed in PARP(+/+) but not in PARP(-/-) myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2alpha deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.
Jyothish B Pillai; Madhu Gupta; Senthilkumar B Rajamohan; Roberto Lang; Jai Raman; Mahesh P Gupta
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-04-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  291     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-09-15     Completed Date:  2006-11-09     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1545-53     Citation Subset:  IM    
Dept. of Surgery, MC 5040, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
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MeSH Terms
Angiotensin II / physiology*
Cardiomegaly / genetics,  physiopathology*,  prevention & control*
Cells, Cultured
Endomyocardial Fibrosis / chemically induced,  pathology,  prevention & control
Gene Expression Regulation, Enzymologic / physiology
Mice, Knockout
Muscle Cells / drug effects,  metabolism,  pathology
Myocardium / metabolism
NAD / metabolism
Oxidative Stress / physiology
Poly(ADP-ribose) Polymerases / genetics*,  physiology
Signal Transduction / genetics,  physiology
Sirtuin 1
Sirtuins / metabolism
Grant Support
Reg. No./Substance:
11128-99-7/Angiotensin II; 53-84-9/NAD; EC Polymerases; EC, mouse; EC 3.5.1.-/Sirt1 protein, mouse; EC 3.5.1.-/Sirtuin 1; EC 3.5.1.-/Sirtuins

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