Abstract 1234: The Unique E-domain of an IGF-I Isoform Expressed in Muscle Preserves Cardiac Function and Prevents Apoptosis following Myocardial Infarction
Insulin like growth factor-I (IGF-I) is expressed as two isoforms in the heart, a major (IGF-IEa) and minor isoform (IGF-IEb), also known as mechano-growth factor (MGF). These isoforms differ in their E-domain region and their expression dynamics during acute myocardial infarction (MGF, sham=0.43±0.14 vs. MI-2.2±0.4*, IGF-IEa, sham=41±1.0 vs. MI=31±3.0 fg, p<0.05, n=6). Therefore, we wish to determine whether the unique E-domain of MGF has biological function. To test this, a synthetic peptide corresponding to the E-domain of MGF was administered 1mg/kg/day via osmotic pump for 2 weeks in mice. Three time points were studied: treatment during acute myocardial infarction (MI), and at 2 and 8 weeks chronic-MI. Four groups were used: sham, sham+E-domain, MI and MI+E-domain (n=6). Cardiac function was assessed by pressure-volume (PV) loop analysis, gene expression by quantitative RT-PCR and the extent of apoptosis by flow cytometry. A significant decline in both systolic and diastolic hemodynamics accompanied by a right shift in the P-V loops and depressed end systolic pressure-volume relationship (ESPVR), occurred in all the MI groups. No differences were noted between control groups. Treatment during acute-MI ameliorated the decline in hemodynamics, whereas treatment during chronic-MI resulted in a significant improvement in contractility (ESPVR and preload recruitable stroke work). Hypertrophy was noted in all the untreated MI groups as increased ANF and β-MHC expression correlated with an increased HW/BW ratio. However, no indication of hypertrophy was observed in the acute-MI treated group. Propidium iodide (PI) and annexin V (AV) staining revealed a greater percent of necrotic and apoptotic myocytes isolated from the untreated acute-MI group compared to the treated group which showed a greater number of viable myocytes (MI, PI= 30%, AV=43%, Viable=27% vs. MI+Edomain PI=1%, AV=43%, Viable=56%, n=4). Our data suggest that administration of the MGF E-domain peptide during acute-MI protects the myocardium by preserving contractile function, preventing pathologic hypertrophy and apoptosis. Also, treatment during chronic-MI improves cardiac function and has therapeutic implications for preventing the progression of ischemic heart failure.