Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Abstract

Oxidant stress-induced activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of various cardiovascular diseases. We have now investigated the role of PARP in the process of cardiac remodeling and heart failure in a mouse model of heart failure induced by transverse aortic constriction (banding). The catalytic activity of PARP was inhibited by the potent isoindolinone-based PARP inhibitor INO-1001 or by PARP-1 genetic deficiency. PARP inhibition prevented the pressure overload-induced decrease in cardiac contractile function, despite the pressure gradient between both carotid arteries being comparable in the two experimental groups. The development of hypertrophy, the formation of collagen in the hearts, and the mitochondrial-to-nuclear translocation of the cell death factor apoptosis-inducing factor (AIF) were attenuated by PARP inhibition. The ability of the inhibitor to block the catalytic activity of PARP was confirmed by immunohistochemical detection of poly(ADP-ribose), the product of the enzyme in the heart. Plasma levels of INO-1001, as measured at the end of the experiments, were in the concentration range sufficient to block the oxidant-mediated activation of PARP in murine cardiac myocytes in vitro. Myocardial hypertrophy and AIF translocation was also reduced in PARP-1-deficient mice undergoing aortic banding, compared with their wild-type counterparts. Overall, the current results demonstrate the importance of poly(ADP-ribos)ylation in the pathogenesis of banding-induced heart failure.Poly(ADP-ribose) polymerase (PARP)-1, a monomeric enzyme present in eukaryotes, is the major isoform of an expanding family of poly(ADP-ribosyl)ating enzymes (for review, see Virá g and Szabó, 2002). The main isoform of the family, PARP-1, primarily functions as a DNA damage sensor in the nucleus. Upon binding to damaged DNA mainly through the second zinc finger domain, PARP-1 forms homodimers and catalyzes the cleavage of NAD ϩ into nicotinamide and ADP-ribose and uses the latter to synthesize branched nucleic acid-like polymers poly(ADP-ribose) covalently attached to nuclear acceptor proteins. The biological role of PARP-1 is complex and includes the regulation of DNA repair and maintenance of genomic integrity.PARP-1 has been implicated in a variety of pathophysiological processes. PARP is an energy-consuming enzyme, which transfers ADP ribose units to nuclear proteins. As a result of this process, the intracellular nicotinamide dinucleotide (oxidized) (NAD ϩ ) and ATP levels remarkably decrease, resulting in cell dysfunction and cell death via the necrotic route (for review, see Virá g and Szabó, 2002).PARP becomes activated in response to DNA single-strand breaks, which can develop as a response to free radical and oxidant cell injury. Oxidative and nitrosative stress triggers the activation of the nuclear enzyme PARP, which contributes to the pathogenesis of various cardiovascular diseases, including myocardial infarction and ischemia-reperfusion and heart failure (for review, s...

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.…”

Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

“…By comparing wild-type and PARP-1-deficient myocytes, they also provided evidence showing that PARP-1 might directly or indirectly be involved in the regulation of AIF translocation subjected to oxidative stress [20]. By using a mouse heart failure model induced by transverse aortic banding, the mitochondrial-to-nuclear translocation of AIF was also exhibited while the extent of translocation was attenuated by inhibition of the activation of PARP-1 either through the isoindolinone-based PARP inhibitor (INO-1001) or PARP-1 genetic deficient mice [22]. While these data have related AIF to the incidence of cardiac apoptosis, it is worthy noting that PARP-1 has been suggested to play an important mediating role in the regulation of the release and translocation of AIF and therefore subsequent activation of caspase-independent apoptosis in ischemia-reperfusion and heart failure [23,22].…”

“…AIF was first discovered as a mitochondrial effector of apoptotic cell death working independently of the caspase machinery [19]. With a focus on the pro-apoptotic role of AIF in cardiovascular diseases, the involvement of AIF have been consistently demonstrated in several different cardiac cell death settings, as, for example, in ischemia-reperfusion, oxidative stress (i.e., hydrogen peroxide) exposure in vitro, and heart failure induced by transverse aortic constriction/banding [20][21][22]. Kim and colleagues [21] demonstrated the accumulation of AIF in the cytosolic and nuclear fractions of heart following ischemia-reperfusion whereas AIF was found to be confined only in mitochondria in control heart.…”

“…By using a mouse heart failure model induced by transverse aortic banding, the mitochondrial-to-nuclear translocation of AIF was also exhibited while the extent of translocation was attenuated by inhibition of the activation of PARP-1 either through the isoindolinone-based PARP inhibitor (INO-1001) or PARP-1 genetic deficient mice [22]. While these data have related AIF to the incidence of cardiac apoptosis, it is worthy noting that PARP-1 has been suggested to play an important mediating role in the regulation of the release and translocation of AIF and therefore subsequent activation of caspase-independent apoptosis in ischemia-reperfusion and heart failure [23,22]. Although the exact role of PARP-1/AIF in cardiac apoptosis is not fully understood, it has been suggested that energy deficit (i.e., depletion of NAD + and ATP) resulting from over-activation of PARP-1 due to oxidative stressinduced DNA damage might be one of the events which initiates the release and translocation of AIF during ischemia-reperfusion [23].…”

Rodent models of heart failure: an updated review

“…1. For instance, in weanling rats [70,263,309,316], a TAC surgery that reduces 50% of the aorta diameter creates a systolic pressure gradient of *50-60 mmHg between the aorta and the LV, inducing clear echocardiographic evidence of LV hypertrophy, and increases left atrial pressure around the 8th week [162]. After 18-20 weeks of compensated LV hypertrophy, a subgroup of animals eventually decreases LV systolic pressure, accompanied by increased LV volume, reduced ejection fraction and clinical signs of overt CHF [309].…”