Submitted on October 4, 2007
Accepted on January 12, 2008
IGF-1 Alleviates Diabetes-Induced RhoA Activation, eNOS Uncoupling and Myocardial Dysfunction
Jun Ren1*, Jinhong Duan2, D. Paul Thomas3, Xiaoping Yang4, Nair Sreejayan1, James R Sowers5, Annarosa Leri6, Jan Kajstura7, Feng Gao, and Piero Anversa8
1 Pharmaceutical Sciences, School of Pharmacy, Laramie, Wyoming, United States
2 United States
3 School of Physical & Health Education, University of Wyoming, Laramie, Wyoming, United States
4 Department of Surgery, University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Ave, Denver, Colorado, 80262, United States
5 United States; , United States
6 Department of Medicine, New York Medical College, Valhalla, New York, United States
7 Cardiovascular Research Institute, New York Medical College, Valhalla, New York, United States
8 Dept. of Medicine, New York Medical College, Valhalla, New York, United States
* To whom correspondence should be addressed. E-mail: jren{at}uwyo.edu.
IGF-1 rescues diabetic heart defects. This study was designed to delineate the beneficial effects of IGF-1 with a focus on RhoA, Akt and eNOS coupling. Echocardiography was performed in normal or diabetic FVB and IGF-1 transgenic mice. Cardiomyocyte contractile properties were evaluated using peak shortening (PS), time-to-90% relengthening (TR90), intracellular Ca2+ rise (
FFI) and decay. Diabetes reduced fraction shortening, PS and FFI, increased chamber size, prolonged TR90 and intracellular Ca2+ decay. Levels of active RhoA and O2- were elevated whereas NO levels were reduced in diabetes. Diabetes-induced O2- accumulation was ablated by the NOS inhibitor L-NAME, indicating eNOS uncoupling, all of which except heart size were negated by IGF-1. The IGF-1-elicited beneficial effects were mimicked by the Rho kinase inhibitor Y27632 and BH4. Diabetes depressed expression of Kv1.2 and DHFR, increased 
-MHC expression, stimulated p38 MAPK, and reduced levels of total Akt and phosphorylated Akt/eNOS, all of which with the exception of MHC were nullified by IGF-1. In addition, Y27632 and the eNOS coupler folate abrogated glucose toxicity-induced PS decline, TR90 prolongation, increased O2-, decreased NO and Kv1.2 levels. The DHFR inhibitor methotrexate impaired myocyte function, NO/O2- balance and nullified Y27632-induced cardiac protection. These results revealed that IGF-1 benefits diabetic hearts via Rho inhibition and antagonism of diabetes-induced decrease in pAkt, eNOS uncoupling and K+ channel expression.
