Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

• Published in: American journal of physiology. Heart and circulatory physiology 2006-10, Vol.291 (4), p.H1545-H1553
• Main Authors: Pillai, Jyothish B, Gupta, Madhu, Rajamohan, Senthilkumar B, Lang, Roberto, Raman, Jai, Gupta, Mahesh P
• Format: Article
• Language: English
• Subjects: ACE inhibitors; Angiotensin II - physiology; Animals; Apoptosis; Cardiomegaly - genetics; Cardiomegaly - physiopathology; Cardiomegaly - prevention & control; Cells; Cells, Cultured; Chromatin; Endomyocardial Fibrosis - chemically induced; Endomyocardial Fibrosis - pathology; Endomyocardial Fibrosis - prevention & control; Enzymes; Gene Expression Regulation, Enzymologic - physiology; Heart failure; Mice; Mice, Knockout; Muscle Cells - drug effects; Muscle Cells - metabolism; Muscle Cells - pathology; Myocardium - metabolism; NAD - metabolism; Oxidative Stress - physiology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - physiology; Signal Transduction - genetics; Signal Transduction - physiology; Sirtuin 1; Sirtuins - metabolism; Studies
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01124.2005

Departments of 1 Surgery and 2 Cardiology, and 3 Committee on Molecular Medicine and Pathology, The University of Chicago, Chicago, Illinois; and 4 The Heart Institute of Children, Hope Children Hospital, Oak Lawn, Illinois Submitted 24 October 2005 ; accepted in final form 12 April 2006 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 µM) 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 µM), 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 Sir2 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. heart failure; oxidative-stress signaling Address for reprint requests and other correspondence: M. P. Gupta, Dept. of Surgery, MC 5040, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 (e-mail: mgupta{at}surgery.bsd.uchicago.edu )