G-Protein Signaling Participates in the Development of Diabetic Cardiomyopathy

G-Protein Signaling Participates in the Development of Diabetic Cardiomyopathy Ian S. Harris 1 , Ilya Treskov 1 , Michael W. Rowley 1 , Scott Heximer 2 , Kevin Kaltenbronn 2 , Brian N. Finck 1 , Richard W. Gross 1 3 , Daniel P. Kelly 1 , Kendall J. Blumer 2 and Anthony J. Muslin 1 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 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 Abstract 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-α (PPAR-α) were examined as a model of diabetic cardiomyopathy. PPAR-α 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-α mice with transgenic mice with cardiac-specific overexpression of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G q and G i . Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-α overexpression without affecting the metabolic abnormalities seen in these hearts. Next, transgenic mice with increased or decreased cardiac G q 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 αq , G αq -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 G q -mediated signaling plays a critical role in the pathogenesis of diabetic cardiomyopathy. ANF, atrial natriuretic factor LV, left ventricular mCPT-1, mitochondrial carnitine palmitoyltrans