Published online before print April 27, 2009, doi: 10.1161/HYPERTENSIONAHA.108.123422
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(Hypertension. 2009;53:1023.)
© 2009 American Heart Association, Inc.
Original Articles |
Metallothionein Abrogates GTP Cyclohydrolase I Inhibition–Induced Cardiac Contractile and Morphological Defects
Role of Mitochondrial Biogenesis
From the Center for Cardiovascular Research and Alternative Medicine (A.F.C.-I., K.K.G., J.R.), University of Wyoming College of Health Sciences, Laramie; School of Medicine and Health Sciences (E.C.C., J.R.P., J.R.), University of North Dakota, Grand Forks; Department of Surgery (S.-J.L., A.F.C.), University of Pittsburgh School of Medicine, and Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pa; and the Department of Pediatrics (L.C.), University of Louisville, Ky.
Correspondence to Jun Ren, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071. E-mail jren{at}uwyo.edu
One key mechanism for endothelial dysfunction is endothelial NO synthase (eNOS) uncoupling, whereby eNOS generates O2•– rather than NO because of deficient eNOS cofactor tetrahydrobiopterin (BH4). This study was designed to examine the effect of BH4 deficiency on cardiac morphology and function, as well as the impact of metallothionein (MT) on BH4 deficiency–induced abnormalities, if any. Friend virus B (FVB) and cardiac-specific MT transgenic mice were exposed to 2,4-diamino-6-hydroxy-pyrimidine (DAHP; 10 mmol/L, 3 weeks), an inhibitor of the BH4 synthetic enzyme GTP cyclohydrolase I. DAHP reduced plasma BH4 levels by 85% and elevated blood pressure in both FVB and MT mice. Echocardiography found decreased fractional shortening and increased end-systolic diameter in DAHP-treated FVB mice. Cardiomyocytes from DAHP-treated FVB mice displayed enhanced O2•– production, contractile and intracellular Ca2+ defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, reduced intracellular Ca2+ rise, and clearance. DAHP triggered mitochondrial swelling/myocardial filament aberrations and mitochondrial O2•– accumulation, assessed by transmission electron microscopy and MitoSOX Red fluorescence, respectively. DAHP also promoted the NG-nitro-L-arginine methyl ester–inhibitable O2•– production and eNOS phosphorylation at Thr497. Although MT had little effect on cardiac mechanics and ultrastructure, it attenuated DAHP-induced defects in cardiac function, morphology, O2•– production, and eNOS phosphorylation (Thr497). The DAHP-induced cardiomyocyte mechanical responses were alleviated by in vitro BH4 treatment. DAHP inhibited mitochondrial biogenesis, mitochondrial uncoupling protein 2, and chaperone heat shock protein 90, and all but uncoupling protein 2 were rescued by MT. Our data suggest a role for BH4 deficiency in cardiac dysfunction and the therapeutic potential of antioxidants against eNOS uncoupling in the heart.
Key Words: BH4 • eNOS uncoupling • cardiomyocyte mechanics • metallothionein • superoxide
Related Article:
Hypertension 2009 53: 907-908.
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  J. Bauersachs and J. D. Widder Tetrahydrobiopterin, Endothelial Nitric Oxide Synthase, and Mitochondrial Function in the Heart Hypertension, June 1, 2009; 53(6): 907 - 908. [Full Text] [PDF]
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