title: Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase.
abstract: BACKGROUND
  Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated.
  
  
  RESULTS
  Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function was preserved compared with the control MI rats.
  
  
  CONCLUSIONS
  The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function.
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tomoya
authors: T
authors: Masano
authors: Seinosuke
authors: S
authors: Kawashima
authors: Ryuji
authors: R
authors: Toh
authors: Seimi
authors: S
authors: Satomi-Kobayashi
authors: Masakazu
authors: M
authors: Shinohara
authors: Tomofumi
authors: T
authors: Takaya
authors: Naoto
authors: N
authors: Sasaki
authors: Masafumi
authors: M
authors: Takeda
authors: Hideto
authors: H
authors: Tawa
authors: Tomoya
authors: T
authors: Yamashita
authors: Mitsuhiro
authors: M
authors: Yokoyama
authors: Ken-ichi
authors: K
authors: Hirata
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D013481:Superoxides; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C003402:sapropterin