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GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

IGF-I alleviates diabetes-induced RhoA activation, eNOS uncoupling, and myocardial dysfunction

¹School of Pharmacy and ³Division of Kinesiology and Health, College of Health Sciences, University of Wyoming, Laramie, Wyoming; ²Department of Physiology, Fourth Military Medical University, Xi'an, China; ⁴University of Missouri-Columbia, Columbia, Missouri; and ⁵New York Medical College, Valhalla, New York

Submitted 4 October 2007 ; accepted in final form 12 January 2008

IGF-I rescues diabetic heart defects and oxidative stress, although the underlying mechanism of action remains poorly understood. This study was designed to delineate the beneficial effects of IGF-I with a focus on RhoA, Akt, and eNOS coupling. Echocardiography was performed in normal or diabetic Friend Virus-B type (FVB) and IGF-I transgenic mice. Cardiomyocyte contractile properties were evaluated using peak shortening (PS), time-to-90% relengthening (TR₉₀), and intracellular Ca²⁺ rise and decay. Diabetes reduced fraction shortening, PS, and intracellular Ca²⁺; it increased chamber size, prolonged TR₉₀, and intracellular Ca²⁺ decay. Levels of RhoA mRNA, active RhoA, and O₂^– were elevated, whereas nitric oxide (NO) levels were reduced in diabetes. Diabetes-induced O₂^– accumulation was ablated by the NO synthase (NOS) inhibitor nitro-L-arginine methyl ester (L-NAME), indicating endothelial NOS (eNOS) uncoupling, all of which except heart size were negated by IGF-I. The IGF-I-elicited beneficial effects were mimicked by the Rho kinase inhibitor Y27632 and BH₄. Diabetes depressed expression of Kv_1.2 and dihydrofolate reductase (DHFR), increased β-myosin heavy-chain expression, stimulated p38 MAPK, and reduced levels of total Akt and phosphorylated Akt/eNOS, all of which with the exception of myosin heavy chain were attenuated by IGF-I. In addition, Y27632 and the eNOS coupler folate abrogated glucose toxicity-induced PS decline, TR₉₀ prolongation, while it increased O₂^– and decreased NO and Kv_1.2 levels. The DHFR inhibitor methotrexate impaired myocyte function, NO/O₂^– balance, and rescued Y27632-induced cardiac protection. These results revealed that IGF-I benefits diabetic hearts via Rho inhibition and antagonism of diabetes-induced decrease in pAkt, eNOS uncoupling, and K⁺ channel expression.

heart; Akt; K⁺ channel; cardiomyocytes; nitric oxide; intracellular Ca²⁺

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