IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress

Stimulation of the local renin-angiotensin system and apoptosis characteriz e the diabetic heart. Because IGF-1 reduces angiotensin (Ang) II and apopto sis, we tested whether streptozotocin-induced diabetic cardiomyopathy was a ttenuated in IGF-1 transgenic mice (TGM). Diabetes progressively depressed ventricular performance in wild-type mice (WTM) but had no hemodynamic effe ct on TGM. Myocyte apoptosis measured at 7 and 30 days after the onset of d iabetes was twofold higher in WTM than in TGM. Myocyte necrosis was apparen t only at 30 days and was more severe in WTM. Diabetic nontransgenic mice l ost 24% of their ventricular myocytes and showed a 28% myocyte hypertrophy; both phenomena were prevented by IGF-1. In diabetic WTM, p53 was increased in myocytes, and this activation of p53 was characterized by upregulation of Bax, angiotensinogen, Ang type 1 (AT(1)) receptors, and Ang II. IGF-1 ov erexpression decreased these biochemical responses. In vivo accumulation of the reactive O-2 product nitrotyrosine and the in vitro formation of H2O2- (OH)-O-. in myocytes were higher in diabetic WTM than TGM. Apoptosis in vit ro mas detected in myocytes exhibiting high H2O2-(OH)-O-. fluorescence, and apoptosis in vivo was Linked to the presence of nitrotyrosine, H2O2-(OH)-O -. generation and myocyte apoptosis in vitro mere inhibited by the AT(1) bl ocker losartan and the O-2 scavenger Tiron. In conclusion, IGF-1 interferes with the development of diabetic myopathy by attenuating p53 function and Ang II production and thus AT(1) activation, This latter event might be res ponsible for the decrease in oxidative stress and myocyte death by IGF-1.