title: Critical role for white blood cell NAD(P)H oxidase-mediated plasminogen activator inhibitor-1 oxidation and ventricular rupture following acute myocardial infarction.
abstract: Plasminogen activator inhibitor-1 (PAI-1) is an oxidant-sensitive protease inhibitor that is inactivated by oxidation and has a critical role in ventricular remodeling post myocardial infarction (MI). PAI-1 knockout (KO) mice die within 7days of myocardial infarction post MI due to increased plasmin activity leading to ventricular rupture. The goal of this study was to assess the relevant pathways of leukocyte-derived oxidants post MI that alter PAI-1 activity. Transplantation of wild-type (WT) bone marrow into PAI-1 null mice prolonged survival after MI (WT marrow: 41.66% vs. PAI-1 KO marrow: 0% in PAI-1 KO mice at day 7 (p<0.02). To determine relevant enzyme systems, we transplanted marrow from mice with specific deletions relevant to leukocyte-derived oxidants (NAD(P)H oxidase, iNOS, myeloperoxidase (MPO)) to determine which deletion controls PAI-1 oxidative inactivation and prolongs survival. MI was induced by ligation of the left anterior descending artery (LAD) and the incidence of cardiac rupture was monitored. PAI-1 KO transplanted with MPO KO, or iNOS KO bone marrow died within 9 days after MI. PAI-1 KO mice transplanted with p47(phox) KO marrow exhibited prolonged survival 21 days after MI (30% survival, p<0.03, n=10) compared to WT marrow (8.3%, n=12). Three days after MI, PAI-1 KO mice transplanted with p47(phox) KO marrow had increased PAI-1 activity and decreased nitration of PAI-1 in myocardial tissue compared to PAI-1 KO mice transplanted with WT marrow. These data suggest that modulating O(2)(•-) generation by NAD(P)H oxidase appears to be a therapeutically relevant target for increasing myocardial PAI-1 levels after MI, whereas downstream enzymes like MPO and iNOS may not be.
authors.affiliation: Department of Cardiovascular Medicine and Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Udit
authors.initials: U
authors.lastname: Agarwal
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
authors.forename: Kristal
authors.initials: K
authors.lastname: Weber
authors.forename: Alisher R
authors.initials: AR
authors.lastname: Dadabayev
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D006341:Heart Rupture / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006342:Heart Rupture, Post-Infarction / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology*; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000097:blood*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases