title: Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy.
abstract: 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.
authors.affiliation: Dept. of Surgery, MC 5040, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
authors.forename: Jyothish B
authors.initials: JB
authors.lastname: Pillai
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.forename: Senthilkumar B
authors.initials: SB
authors.lastname: Rajamohan
authors.forename: Roberto
authors.initials: R
authors.lastname: Lang
authors.forename: Jai
authors.initials: J
authors.lastname: Raman
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D002478:Cells, Cultured; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism
chemical_list: D009243:NAD; D000804:Angiotensin II; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins