title: Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection.
abstract: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), and reduced BH4 availability leads to endothelial NOS (eNOS) uncoupling and increased reactive oxygen species (ROS) generation. Questions remain regarding the functional state of eNOS and role of BH4 availability in the process of in vivo myocardial ischemia-reperfusion (I/R) injury. Rats were subjected to 60min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic liposomal BH4 supplementation (1mg/kg, iv). Myocardial infarction was correlated with cardiac BH4 content, eNOS protein level, NOS enzyme activity, and ROS generation. In the vehicle group, 60-min ischemia drastically reduced myocardial BH4 content in the area at risk (AAR) compared to non-ischemic (NI) area and the level remained lower during early reperfusion followed by recovery after 24-h reperfusion. Total eNOS, activated eNOS protein level (eNOS Ser1177 phosphorylation) and NOS activity were also significantly reduced during ischemia and/or early reperfusion, but recovered after 24-h reperfusion. With liposomal BH4 treatment, BH4 levels were identical in the AAR and NI area during ischemia and/or early reperfusion, and were significantly higher than with vehicle. BH4 pre-treatment preserved eNOS Ser1177 phosphorylation and NOS activity in the AAR, and significantly reduced myocardial ROS generation and infarction compared to vehicle. These findings provide direct evidence that in vivo I/R induces eNOS dysfunction secondary to BH4 depletion, and that pre-ischemic liposomal BH4 administration preserves eNOS function conferring cardioprotection with reduced oxidative stress.
authors.affiliation: Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA; The Institute of Organ Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: M A Hassan
authors.initials: MA
authors.lastname: Talukder
authors.affiliation: Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Saradhadevi
authors.initials: S
authors.lastname: Varadharaj
authors.affiliation: Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address: jay.zweier@osumc.edu.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000818:Animals; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D001708:Biopterins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin
keywords: Ischemia/reperfusion; Myocardial BH(4) content; Myocardial protection; NOS activity; Oxidative stress; Tetrahydrobiopterin