Attenuation of Post-infarct Cardiac Hypertrophy by Allogeneic Cell-mediated Supplemental Igf-1 Propeptide Delivery

Background: Cardiovascular remodelling after myocardial infarction leads to cardiac function impairment due to left ventricle dilation, distortion of ventricular shape and mural hypertrophy. Therefore, ventricular remodelling can be considered a primary target for therapeutic treatment. We previously documented that cardiac-specific overexpression of the propeptide insulin-like growth factor 1Ea (IGF-1Ea) contributed to beneficial cardiac repair after ischemic damage by employing anti-inflammatory and antioxidant molecules, decreasing scar formation and enhancing cardiac function. The above benefits suggest that IGF-1 may be therapeutically important in cardiovascular diseases. However, the precise mechanisms in clinical-like procedures are not yet elucidated and IGF-1 family of growth factors are therefore poorly recognized pharmacologically. We hypothesized that IGF-1Ea-mediated delivery by allogeneic cell therapy could favour long-term decrease of left ventricle remodelling after myocardial infarction. Methods and Results: To support long-term expression of the propeptide IGF-1Ea, we infected pluripotent P19Cl6-MLC2vGFP cells with a lentivirus carrying the Igf-1Ea gene under the CMV promoter. These cells, which efficiently differentiate into cardiomyocytes activating a GFP transgene, were injected into the ventricular wall of C57BL/6 mice (n=11) after myocardial infarct induction in an allogeneic transplantation model. Mice injected with cells not expressing the transgene were used as control. IGF-1Ea delivery improved long-term local systolic function measured as percentage of anterior wall motion (60% vs 20%, p<0.01) and correlated with increased cell retention, decreased hypertrophic response through downregulation of the angiotensin signalling and activated pro-angiogenic program compared to mice transplanted with cells not expressing the transgene. Conclusions: this study indicates that allogeneic cell-mediated IGF-1Ea delivery is a good candidate in pharmacological and clinical studies to contribute to long-term beneficial remodelling of the heart in response to myocardial infarct.