title: Poly (ADP-ribose) polymerase-1: an emerging target in right ventricle dysfunction associated with pulmonary hypertension.
abstract: Recently, inhibition of poly (ADP-ribose) polymerase-1 (PARP1) was shown to be protective in experimental pulmonary hypertension (PH) and prevented right ventricular hypertrophy (RVH) associated with it. However, molecular mechanism behind cardioprotection by PARP1 inhibition in PH still needs detailed exploration. Therefore, effect of inhibition of PARP1 on the right ventricle (RV) dysfunction was studied in monocrotaline (MCT) induced PH model. Following a single dose administration of MCT (60 mg/kg, s.c.), male Sprague-Dawley rats were treated with PARP1 inhibitor 1,5-Isoquinolinediol (ISO, 3 mg/kg, i.p.) for 35 days for preventive study and from day 21-35 for curative study. RV pressure (RVP) and RVH were measured after 35 days. Histophathological studies, PARP1 activity, mRNA and protein expression were studied in isolated RV. Oxidative and nitosative stress, inflammation and Matrix metalloproteinases (MMPs)/Tissue inhibitor of metalloproteinase 2 (TIMP2) were also assessed. Mitochondrial dysfunction was studied by mitochondrial membrane permeability and estimation of Nicotinamide adenine dinucleotide (NAD) and Adenosine triphosphate (ATP). Apoptosis in RV was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase 3 activity and cleaved PARP1 expression. PARP1 inhibition significantly reversed the increase in RVP and RVH in both preventive and curative treatment in the MCT-injected rats. ISO lowered oxidative and nitrosative stress and inflammation and restored the balance of MMPs/TIMP2 expression. PARP1 inhibition prevented mitochondrial dysfunction and the release of cell death factors from mitochondria. ISO also decreased apoptosis by decreasing number of TUNEL positive cells, caspase 3 activity and PARP1 cleavage in RV. Thus, PARP1 inhibition ameliorated PH induced RV hypertrophy and may emerge as a new therapeutic target for PH.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Faculty of Pharmacy, Integral University, Lucknow 226001, India.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.affiliation: National Institute of Pharmaceutical Education and Research, Rae Bareli 229010, India.
authors.forename: Poorella
authors.initials: P
authors.lastname: Lingeshwar
authors.affiliation: Faculty of Pharmacy, Integral University, Lucknow 226001, India.
authors.forename: Hefazat H
authors.initials: HH
authors.lastname: Siddiqui
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; National Institute of Pharmaceutical Education and Research, Rae Bareli 229010, India; Academy of Scientific and Innovative Research, New Delhi, India. Electronic address: k_hanif@cdri.res.in.
authors.forename: Kashif
authors.initials: K
authors.lastname: Hanif
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D016686:Monocrotaline / Q000633:toxicity; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D019716:Tissue Inhibitor of Metalloproteinase-2; C095653:1,5-dihydroxyisoquinoline; D016686:Monocrotaline; D000255:Adenosine Triphosphate; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: Apoptosis; Mitochondrial dysfunction; Poly (ADP-ribose) polymerase-1; Pulmonary hypertension; Right ventricle hypertrophy; Right ventricle pressure