Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy. Sci Rep 2016 Jun 13;6:27925
Date
06/15/2016Pubmed ID
27295516Pubmed Central ID
PMC4904741DOI
10.1038/srep27925Scopus ID
2-s2.0-84974802688 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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.
Author List
Wu HE, Baumgardt SL, Fang J, Paterson M, Liu Y, Du J, Shi Y, Qiao S, Bosnjak ZJ, Warltier DC, Kersten JR, Ge ZDMESH terms used to index this publication - Major topics in bold
AnimalsBlood Pressure
Calcium Signaling
Diabetes Mellitus, Experimental
Diabetic Cardiomyopathies
Disease Models, Animal
GTP Cyclohydrolase
Hemodynamics
Hypoxanthines
Leupeptins
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardium
Myocytes, Cardiac
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III
Streptozocin
Ventricular Remodeling
p38 Mitogen-Activated Protein Kinases
