Abstract 13380: Administration of Insulin-Like Growth Factor Prevents Cardiac Dysfunction and Expression of microRNA-1 in Apolipoprotein-E null Mice with Streptozotocin -Induced Diabetes
Background: Many microRNA (miR) species have been found to serve as biomarkers, modulators or therapeutic targets for cardiovascular disease (CVD). Among them, miR-1 is preferentially expressed in cardiac muscles, and has been shown to contribute to myocardial dysfunction. On the other hand, insulin-like growth factor (IGF-1) is cardiac protective. Diabetic injury can accelerate atherosclerotic coronary disorder. This study was designed to test the impact of IGF-1 on miR-1 expression in the heart of apolipoprotein-E null (ApoE-/-) mice with drug induced diabetes.
Methods and Results: Diabetes was induced in C57BL mice (without dyslipidemia), and ApoE-/- atherosclerosis-prone mice by injecting streptozotocin (STZ). There was increased inflammation (increased expression of TNF-alpha and IL-6) found in both diabetic C57BL/STZ and ApoE-/-/STZ mice. Also, the levels of circulating IGF-1 were reduced, and early development of cardiac dysfunction (reduced fractional shortening and E/A ratio) were found in ApoE-/-/STZ mice. In diabetic ApoE-/-/STZ mice, the myocardium exhibited increased levels of miR-1 (mirVana qRT-PCR miRNA detection assay), and decreased expression of IGF-1 protein (Western blot). In diabetic ApoE-/-/STZ mice, IGF-1 infusion restored cardiac function. The improvement of cardiac function by IGF-1 treatment was co-occurring with reduced cytochrome c release and cardiac apoptosis. IGF-1 treatment decreased the pro-apoptotic protein caspase 3, but increased levels of anti-apoptotic protein bcl-2 in the hearts. Following IGF-1 infusion, the cardiac miR-1 levels declined. IGF-1 receptor siRNA treatment in cultured myocyte revealed that IGF-1 decreased miR-1 expression via IGF-1 receptor signaling in a PI3/Akt dependent manner.
Conclusion: Compared to C57BL mice with STZ-induced diabetes, ApoE-/-/STZ diabetic mice showed reduced levels of circulating IGF-1 but increased expression of miR-1 and apoptosis in the hearts. IGF-1 infusion in diabetic ApoE-/-/STZ mice might reduce miR-1 expression and apoptosis, and partially restore cardiac function. These findings establish a new paradigm for biological effects of IGF-1, and have major implications for treating atherosclerotic coronary disease with diabetes.
- © 2011 by American Heart Association, Inc.