Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure
P.ál Pacher, MD, PhD*,
Lucas Liaudet, MD  ,
Jon G. Mabley, PhD*,
Katalin Komjáti, MD, PhD*, and
Csaba Szabó, MD, PhD*,*
* Inotek Pharmaceuticals Corporation, Beverly, Massachusetts, USA
Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey, USA
Institute of Human Physiology and Experimental Research, Semmelweis University, Budapest, Hungary
Critical Care Division, Department of Internal Medicine, University Hospital, Lausanne, Switzerland
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Figure 1 Proposed role of poly(adenosine diphosphate-ribose) polymerase (PARP) in oxidant-induced cellular dysfunction and necrosis. Oxygen and nitrogen-derived radicals cause stand breaks in deoxyribonucleic acid (DNA), activating PARP. Activation of PARP initiates an energy-consuming cycle by transferring adenosine diphosphate-ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear proteins resulting in rapid depletion of the intracellular NAD+ and adenosine triphosphate (ATP) pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death. ADPR = adenosine diphosphate-ribose; NADH = reduced nicotinamide adenine dinucleotide; ONOO– = peroxynitrite.
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Figure 2 Improvement of cardiac dysfunction by pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase 10 weeks after permanent ligation of left anterior descending coronary artery in a rat model of chronic heart failure (CHF). Effect of CHF and PJ34 on left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), left ventricular +dP/dt, left ventricular –dP/dt in rats. Results are mean ± 95% confidence interval of 8 to 10 experiments in each group. *p < 0.05 vs. S; #p < 0.05 vs. CHF. BP = blood pressure; CHF + PJ34 = chronic heart failure treated with PJ34 (for 10 weeks); S = sham; S + PJ34 = sham treated with PJ34 (for 10 weeks).
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Figure 3 Effect of pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase on cardiac remodeling and lung weight in rat model of chronic heart failure (CHF) induced by permanent ligation of left anterior descending (LAD) coronary artery. Left ventricular (LVW), right ventricular (RVW), left atrial (LAW), right atrial (RAW), and lung (LungW) weights in sham (S), PJ34-treated (for 10 weeks) sham (S + PJ34), CHF and PJ34-treated (for 10 weeks) CHF (CHF + PJ34) rats. Results are mean ± 95% confidence interval of 8 to 10 experiments in each group. The weight of each cavity and lung was normalized to the length of the right tibia. *p < 0.05 vs. S; #p < 0.05 vs. CHF.
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Figure 4 Evidence for increased nitrotyrosine (NT) formation in hearts from rats with chronic heart failure (CHF). Immunohistochemical staining for NT, an indicator of peroxynitrite formation, in sham (a), CHF (b), and PJ34-treated CHF (c) rat hearts. Panel b shows widespread NT formation in myocytes and intramural vasculature in rats with CHF. Treatment with PJ34 for 10 weeks (c) did not reduce NT formation in rat hearts with CHF. Similar immunohistochemical profiles were seen in n = 4 to 5 hearts per group.
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Figure 5 Evidence for poly(adenosine diphosphate-ribose) polymerase (PARP) activation in hearts from rats with chronic heart failure (HF). Immunohistochemical staining for poly(ADP-ribose) formation, an indicator of PARP activation, in sham (a), CHF (b), and PJ34-treated CHF (c) rat hearts. Panel b shows poly(ADP-ribose) formation localized in the nuclei of myocytes and endothelial cells in rats with CHF. Treatment with PJ34 for 10 weeks (c) markedly reduced PARP activation in rats hearts with CHF. Similar immunohistochemical profiles were seen in six to eight hearts per group.
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Figure 6 Reversal of chronic heart failure (CHF)-induced endothelial dysfunction by pharmacologic inhibition of poly(ADP-ribose) polymerase (PARP) in rats: epinephrine-induced contractions (middle), acetylcholine-induced endothelium-dependent relaxation (upper), and sodium nitroprusside (SNP)-induced endothelium-independent relaxations (lower). Each point of the curve represents mean ± 95% confidence interval of 7 to 10 experiments in vascular rings. *p < 0.05 vs. S; #p < 0.05 vs. CHF. S = sham.
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