Poly(ADP-ribose) Polymerase (PARP) and PARP Inhibitors: Mechanisms of Action and Role in Cardiovascular Disorders

Abstract

Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl-ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free oxygen and nitrogen radicals, the rapid transcriptional activation of inflammatory cytokines, and the activation of PARP1. Inhibition of PARP attenuates neutrophil infiltration and inflammatory cytokine expression in the reperfused myocardium and preserves myocardial NAD+ and ATP. In addition, PARP inhibition increases the activation of myocyte survival enzymes protein kinase B (Akt) and protein kinase C epsilon (PKCε), and decreases the activity of myocardial ventricular remodeling enzymes PKCα/β, PKCζ/λ, and PKCδ. As a consequence, cardiomyocyte and vascular endo...

The E3 ubiquitin ligase Smurf2 regulates PARP1 stability to alleviate oxidative stress‐induced injury in human umbilical vein endothelial cells

“…PARP1 is closely related to DNA damage repair under stress conditions . PARP1 is cut by caspase3 in apoptosis, which eliminates the enzymatic activity of PARP1, thus completing the biological process of apoptosis . The stability of single‐ or double‐stranded DNA is reduced or broken in conditions of oxidative stress damage, which activates PARP1.…”

“…DNA damage caused by ROS and nitrogen species (RNS) is the classical pathway of PARP1 activation . In H 2 O 2 ‐induced cellular oxidative stress damage, cellular DNA breaks, and DNA fragments bind to PARP1 to form a ribosyl‐ribosyl linkage, acting as a signal for other enzymes involved in DNA repair and DNA base repair . However, PARP1 overactivation results in the depletion of NAD + stored in the cell, which slows glycolysis and electron transfer rates, ultimately affecting the formation of ATP in the cell .…”

“…PARP1 is a highly conserved protein approximately 116 kD in size. Previous literature has reported that PARP1, a cleavage substrate of caspase3, plays an irreplaceable role in apoptosis . In the cardiovascular system, the activation of PARP1 is often detrimental.…”

ADP-ribosylation: from molecular mechanisms to human disease

“…PARP1-dependent cell death via parthanatos has been implicated in several critical pathological processes, such as ischemia-reperfusion injury in myocardial infarction and stroke, septic shock, brain trauma and neurodegenerative diseases such as Parkinsons disease and Alzheimers disease (Pacher and Szabo, 2007;Moroni, 2008;Lee et al, 2013;Dawson and Dawson, 2017;Berger et al, 2018;Henning et al, 2018;Kam et al, 2018;Zhang, J. et al, 2018). A common theme among these disorders seems to be PARP1 hyperactivation in response to oxidative DNA damage, either as part of the reperfusion of oxygen-deprived tissues or caused by pathophysiological changes that induce the production of reactive oxygen species or nitric oxide.…”

“…Mounting pre-clinical evidence suggests that PARP1 knockout or PARP inhibitor treatment have profound beneficial effects in mouse models of parthanatos-induced pathologies, preventing cell death and tissue dysfunction (Pacher and Szabo, 2007;Dawson and Dawson, 2017;Berger et al, 2018;Henning et al, 2018). These results have prompted calls for clinical trials to repurpose PARP inhibitors for the treatment of these disorders, particularly when no other viable treatment option exists (Berger et al,8 Hoch and Polo 2018).…”