title: Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of             pressure overload.
abstract: Sustained cardiac pressure overload induces mitochondrial dysfunction and             apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction.             Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces             reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the             cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes             in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac             pressure overload was generated by abdominal aortic banding in rats. Levels of             BH4 and its oxidized form were measured in the mitochondria isolated from the             left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding             increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably,             the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria,             but not in the post-mitochondrial supernatants containing the cytosol and microsome.             Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria.             Moreover, continuous administration of BH4 to rats with pressure overload increased             mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase             activity, but not cardiac hypertrophy. These findings show the possibility that             NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at             least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction             induced by pressure overload.
authors: Department of Pathophysiology, Showa University School of Pharmacy, Tokyo 142-8555, Japan. shun@pharm.showa-u.ac.jp
authors: Shunichi
authors: S
authors: Shimizu
authors: Masaaki
authors: M
authors: Ishibashi
authors: Sumito
authors: S
authors: Kumagai
authors: Teruaki
authors: T
authors: Wajima
authors: Toshihito
authors: T
authors: Hiroi
authors: Tatsuya
authors: T
authors: Kurihara
authors: Masakazu
authors: M
authors: Ishii
authors: Yuji
authors: Y
authors: Kiuchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D062186:Arterial Pressure; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin