Increased expression of poly(ADP-ribose) polymerase-1 contributes to caspase-independent myocyte cell death during heart failure.
Poly(ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in regulating genome stability, cell cycle progression, and cell survival. However, overactivation of PARP has been shown to contribute to cell death and organ failure in various stress-related disease conditions. In this study, we examined the role of PARP in the development and progression of cardiac hypertrophy. We measured the expression of PARP in mouse hearts with physiological (swimming exercise) and pathological (aortic banding) cardiac hypertrophy as well as in human heart samples taken at the time of transplantation. PARP levels were elevated both in swimming and banded mice hearts and demonstrated a linear positive correlation with the degree of cardiac hypertrophy. A dramatic increase (4-fold) of PARP occurred in 6-wk banded mice, accompanied by apparent signs of ventricular dilation and myocyte cell death. PARP levels were also elevated (2- to 3-fold) in human hearts with end-stage heart failure compared with controls. However, we found no evidence of caspase-mediated PARP cleavage in either mouse or human failing hearts. Overexpression of PARP in primary cultures of cardiac myocytes led to suppression of gene expression and robust myocyte cell death. Furthermore, data obtained from the analysis of PARP knockout mice revealed that these hearts produce an attenuated hypertrophic response to aortic banding compared with controls. Together, these results demonstrate a role for PARP in the onset and progression of cardiac hypertrophy and suggest that some events related to cardiac hypertrophy growth and progression to heart failure are mediated by a PARP-dependent mechanism.
Pillai
Jyothish B
JB
Department of Cardiothoracic Surgery, Committee on Molecular Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Russell
Hyde M
HM
Raman
Jai
J
Jeevanandam
Valluvan
V
Gupta
Mahesh P
MP
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism
D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases