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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/R793    most recent 00713.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ren, J. Articles by Anversa, P. PubMed PubMed Citation Articles by Ren, J. Articles by Anversa, P.

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⁺