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

Abstract

-(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 291: H1545-H1553, 2006. First published April 21, 2006 doi:10.1152/ajpheart.01124.2005.-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 ϩ/ϩ ) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-totibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP ϩ/ϩ but not in PARP Ϫ/Ϫ mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP Ϫ/Ϫ cardiomyocytes, angiotensin II (1 M) treatment significantly increased protein synthesis in PARP ϩ/ϩ myocytes, as measured by 3 Hleucine 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 M), robust myocyte cell death was observed in PARP ϩ/ϩ but not in PARP Ϫ/Ϫ 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 IN SETTINGS OF sustained hemodynamic overload, myocardium undergoes a growth response, termed as cardiac hypertrophy. This process is characterized by an increase in myocyte cell size and alterations in expression of contractile and Ca 2ϩ -handling proteins. Cardiac hypertrophy initially develops as an adaptive response; however, if remained unchecked, this eventually progresses to ventricular dilation and pump dysfunction (12). At the biochemical level, many hypertrophy agonists have been identified; among them, angiotensin II has been established as a most potent stimulator of cardiac hypertrophy. Multiple signaling pathways that regulate angiotensin II-mediated cardiac hypertrophy response have been also identified; these include activation of PKC, MAPKs, and the production of reactive oxygen and nitrogen species (30). However, the downstream targets and nuclear integrators of angiotensin II-mediated cardiac growth response are not yet understood.Po...

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…PARP1, a prototype member of the large PARP family, has been shown to interact with TEF1 to form a complex on M-CAT binding sites of the cardiac troponinT and MHC genes, leading to their muscle-specific gene regulation [136,137]. We as well as others have previously reported that PARP1 is activated during both physiologic and pathologic hypertrophy, and that its levels are further elevated in failing hearts [107,135,138]. A linear correlation was found between the intensity of PARP1 activation and the degree of cardiac hypertrophy, suggesting that the magnitude of PARP activation may have a role in the induction and progression of hypertrophy (Fig.…”

“…PARP1 induction was also observed in cell-culture models of cardiac hypertrophy induced by treatment of cells with agonists such as angiotensin-II and phenylephrine [135,139]. In regard to what is known about the intracellular stimuli of PARP1, at least two signaling pathways, an increased intracellular Ca 2+ level and the activation of ERK1/2, have been found to activate PARP1 during hypertrophy [140,141].…”

“…In addition to HAT and HDACs, another family of chromatin modifying enzymes, called poly (ADP-ribose) polymerase (PARP), has been found to play a role in the development of cardiac hypertrophy and MHC gene regulation [107,134,135]. PARP1, a prototype member of the large PARP family, has been shown to interact with TEF1 to form a complex on M-CAT binding sites of the cardiac troponinT and MHC genes, leading to their muscle-specific gene regulation [136,137].…”

Novel modulators of poly(ADP-ribose) polymerase

“…ionizing radiation and genotoxic compounds) [4]. Conditions that can produce reactive radicals and oxidants within the cell, including hypoxia-reoxygenation [5], elevated extracellular glucose concentration [6][7][8][9], Ca 2+ [10] and angiotensin II [11,12], have been identified as endogenous activators of PARP. Allosteric regulation of auto(poly-ADP-ribosyl) ation by Mg 2+ , Ca 2+ , polyamines, ATP and the histones H 1 and H 3 has also been demonstrated [13].…”

Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes

“…PARP-1 is involved in pathophysiologies such as hypertension, stroke, neuronal injury, diabetes and inflammation [24] thereby contributing to similar disease states as the RAS. Consistently, animal experiments indicated that cardiac hypertrophy and also endothelial dysfunction induced by angiotensin II are absent in homozygous PARP-1 deficient mice [25,26]. Nevertheless, the regulatory mechanisms of this RAS-PARP interplay are largely unknown.…”