Abstract 3012: Insulin-like Growth Factor-1 Deficient Mice Exhibit Resistance to Abdominal Aortic Constriction-induced Cardiac Hypertrophy and Contractile Dysregulation: Role of Microrna-1, Microrna-133a and Microrna-208
MicroRNAs are newly found, small, noncoding RNAs which can negative control posttranscrip-tional gene expression. MicroRNA-1, R133a and −208 are specially expressed in heart and contribute to cardiac hypertrophy and stress-dependent cardiac growth. Insulin-like growth factor 1 (IGF-1) plays a key role in the regulation of cardiac growth and function although its interplay with microRNA is unknown. This study was designed to examine the impact of IGF-1 deficiency on abdominal aortic constriction-induced changes in cardiac geometry and function with a focus on microRNAs. Liver IGF-1 deficient (LID) and wild-type C57/BL6 mice were subject to abdominal aortic constriction surgery. Echocardiographic and cardiomyocyte function were assessed 4 weeks later. H&E staining was used to detect myocardial morphology. Expression of hypertrophy markers was determined by western blot. Ventricular microRNA levels were detected using reverse transcription-PCR (RT-PCR). Our data revealed that C57 mice following abdominal aortic constriction displayed increased ventricular diastolic wall thickness, decreased left ventricular end diastolic dimension (LVEDD), elevated cardiomyocyte peak shortening (PS), and enhanced maximal velocity of shortening/relengthening (±dL/dt), in addition to the enhanced heart weight-to-body weight ratio and cardiomyocyte size, all of which were attenuated or nullified in LID mice. Meanwhile, atrial natriuretic peptide (ANP) and GATA-4 expression were elevated following abdominal aortic constriction in C57 but not LID mice. Following surgery, Akt phosphorylation was enhanced in both groups with a greater response in C57 mice whereas glycogen synthase kinase (GSK)-3β and mammalian target of rapamycin (mTOR) phosphorylation remained unchanged. Importantly, levels of microRNA-1, microRNA-133a and microRNA-208 were attenuated by the surgery in C57 mice, the effects of which were ablated by IGF-1 deficiency. Our data suggest that IGF-1 deficiency is capable of retarding aortic constriction-induced cardiac hypertrophy and contractile dysregulation, possibly by alleviating downregulated microRNA-1, microRNA-133a and microRNA-208 levels in response to left ventricular pressure overload (support by NIH P20RR016474).