期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 48, 期 4, 页码 663-672出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2009.11.017
关键词
GLUT4 knockout; Cardiomyocyte; Calcium homeostasis; Myocardial insulin resistance; pH regulation; Excitation-contraction coupling; NCX; NHE
资金
- National Health and Medical Council of Australia (NHMRC)
- Roche Research Foundation
- Swiss National Science Foundation
- University of Melbourne
- Australian Development Scholarship [390000200]
- NHMRC
There is clinical evidence to suggest that impaired myocardial glucose uptake contributes to the pathogenesis of hypertrophic, insulin-resistant cardiomyopathy. The goal of this study was to determine whether cardiac deficiency of the insulin-sensitive glucose transporter, GLUT4, has deleterious effect on cardiomyocyte excitation-contraction coupling. Cre-Lox mouse models of cardiac GLUT4 knockdown (KD, 85% reduction) and knockout (KO, >95% reduction), which exhibit similar systemic hyperinsulinemic and hyperglycemic states, were investigated. The Ca2+ current (I-ca) and Na+-Ca2+ exchanger (NCX) fluxes, Na+-H+ exchanger (NHE) activity, and contractile performance of GLUT4-deficient myocytes was examined using whole-cell patch-clamp, epifluorescence, and imaging techniques. GLUT4-KO exhibited significant cardiac enlargement characterized by cardiomyocyte hypertrophy (40% increase in cell area) and fibrosis. GLUT4-KO myocyte contractility was significantly diminished, with reduced mean maximum shortening (5.0 +/- 0.4% vs. 6.2 +/- 0.6%, 5 Hz). Maximal rates of shortening and relaxation were also reduced (20-25%), and latency was delayed. In GLUT4-KO myocytes, the Ica density was decreased (-2.80 +/- 0.29 vs. -5.30 +/- 0.70 pA/pF), and mean I-NCX was significantly increased in both outward (by 60%) and inward (by 100%) directions. GLUT4-KO expression levels of SERCA2 and RyR2 were reduced by approximately 50%. NHE-mediated H+ flux in response to NH4Cl acid loading was markedly elevated GLUT4-KO myocytes, associated with doubled expression of NHE1. These findings demonstrate that, independent of systemic endocrinological disturbance, cardiac GLUT4 deficiency per se provides a lesion sufficient to induce profound alterations in cardiomyocyte Ca2+ and pH homeostasis. Our investigation identifies the cardiac GLUT4 as a potential primary molecular therapeutic target in ameliorating the functional deficits associated with insulin-resistant cardiomyopathy. (c) 2009 Elsevier Ltd. All rights reserved.
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