Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy.
Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin, and control animals were given citrate buffer. We found that diabetes-induced degradation of cardiac GCH1 proteins contributed to adverse cardiac remodeling and dysfunction in C57BL/6 mice, concomitant with decreases in tetrahydrobiopterin, dimeric and phosphorylated neuronal nitric oxide synthase, sarcoplasmic reticulum Ca(2+) handling proteins, intracellular [Ca(2+)]i, and sarcoplasmic reticulum Ca(2+) content and increases in phosphorylated p-38 mitogen-activated protein kinase and superoxide production. Interestingly, GCH-1 overexpression abrogated these detrimental effects of diabetes. Furthermore, we found that MG 132, an inhibitor for 26S proteasome, preserved cardiac GCH1 proteins and ameliorated cardiac remodeling and dysfunction during diabetes. This study deepens our understanding of impaired cardiac function in diabetes, identifies GCH1 as a modulator of cardiac remodeling and function, and reveals a new therapeutic target for diabetic cardiomyopathy.
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.|National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MA 21224, USA.
Hsiang-En
HE
Wu
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Shelley L
SL
Baumgardt
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Juan
J
Fang
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Mark
M
Paterson
Department of Medicine, Columbia University, 630 W. 168th Street, New York, NY 10032, USA.
Yanan
Y
Liu
Department of Biochemistry, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
Jianhai
J
Du
Aurora Research Institute, Aurora Health Care, 750 W. Virginia Street, Milwaukee, WI 53234, USA.
Yang
Y
Shi
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Shigang
S
Qiao
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.|Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Zeljko J
ZJ
Bosnjak
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
David C
DC
Warltier
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Judy R
JR
Kersten
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Zhi-Dong
ZD
Ge
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020013:Calcium Signaling; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007042:Hypoxanthines / Q000494:pharmacology; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007042:Hypoxanthines; D007976:Leupeptins; D013311:Streptozocin; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D006136:GTP Cyclohydrolase; C000597358:Gch1 protein, mouse; C017202:2,4-diaminohypoxanthine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde