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Diabetes 53:3082-3090, 2004
© 2004 by the American Diabetes Association, Inc.

G-Protein Signaling Participates in the Development of Diabetic Cardiomyopathy

Ian S. Harris1, Ilya Treskov1, Michael W. Rowley1, Scott Heximer2, Kevin Kaltenbronn2, Brian N. Finck1, Richard W. Gross1,3, Daniel P. Kelly1, Kendall J. Blumer2, and Anthony J. Muslin1,2

1 Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
2 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
3 Division of Bio-Organic Chemistry, Washington University School of Medicine, St. Louis, Missouri

Diabetic patients develop a cardiomyopathy that consists of ventricular hypertrophy and diastolic dysfunction. Although the pathogenesis of this condition is poorly understood, previous studies implicated abnormal G-protein activation. In this work, mice with cardiac overexpression of the transcription factor peroxisome proliferator–activated receptor-{alpha} (PPAR-{alpha}) were examined as a model of diabetic cardiomyopathy. PPAR-{alpha} transgenic mice develop spontaneous cardiac hypertrophy, contractile dysfunction, and "fetal" gene induction. We examined the role of abnormal G-protein activation in the pathogenesis of cardiac dysfunction by crossing PPAR-{alpha} mice with transgenic mice with cardiac-specific overexpression of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for Gq and Gi. Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-{alpha} overexpression without affecting the metabolic abnormalities seen in these hearts. Next, transgenic mice with increased or decreased cardiac Gq signaling were made diabetic by injection with streptozotocin (STZ). RGS4 transgenic mice were resistant to STZ-induced cardiac fetal gene induction. Transgenic mice with cardiac-specific expression of mutant G{alpha}q, G{alpha}q-G188S, that is resistant to RGS protein action were sensitized to the development of STZ-induced cardiac fetal gene induction and bradycardia. These results establish that Gq-mediated signaling plays a critical role in the pathogenesis of diabetic cardiomyopathy.

Address correspondence and reprint requests to Dr. Anthony J. Muslin, Box 8086, 660 South Euclid Ave., St. Louis, MO 63110. E-mail: amuslin{at}imgate.wustl.edu


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Copyright © 2004 by the American Diabetes Association.