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

• Published in: Cardiovascular toxicology 2018-12, Vol.18 (6), p.493-506
• Main Authors: Henning, Robert J., Bourgeois, Marie, Harbison, Raymond D.
• Format: Article
• Language: English
• Subjects: Adenine; Adenosine diphosphate; Adhesion; Adhesive bonding; ADP-ribosylation; AKT protein; Angioplasty; Animal models; Animals; Apoptosis; Arteries; Arteriosclerosis; Atherosclerosis; ATP; Biomedical and Life Sciences; Biomedicine; Blood pressure; Breakage; c-Jun protein; Cardiology; Cardiomyocytes; Cardiovascular Agents - adverse effects; Cardiovascular Agents - therapeutic use; Cardiovascular disease; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - enzymology; Cardiovascular Diseases - pathology; Cardiovascular Diseases - physiopathology; Cardiovascular System - drug effects; Cardiovascular System - enzymology; Cardiovascular System - pathology; Cardiovascular System - physiopathology; Caspase; Caspase-3; Catalytic activity; Cell activation; Cell adhesion molecules; Cell death; Cerebral infarction; Coronary artery disease; Cytokines; Damage; Deoxyribonucleic acid; Depletion; Disease Models, Animal; DNA; DNA Damage; DNA repair; DNA Repair - drug effects; Endothelium; Energy Metabolism - drug effects; Enzymes; Gangrene; Heart; Heart attacks; Heart failure; Humans; Infiltration; Inflammation; Inhibition; Inhibitors; Isoforms; JNK protein; Kinases; Molecular chains; Myocardial infarction; Myocardium; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Necrosis; Nitrogen; Oxidative Stress - drug effects; Permeability; Pharmacology/Toxicology; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Proteins; Radicals; Signal Transduction - drug effects; Stroke; Stroke volume; Survival; Targeted cancer therapy; Transcription factors; Ventricle
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-018-9462-2

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 oxy