Abstract 12313: IGF-1 Prevents Oxidative Stress Induced-Mitochondria Dysfunction and Cell Cycle Arrest in Human Cardiac Progenitor Cells via P53/PGC Pathway
Background: Cardiac progenitor cells (CPC) can repair and regenerate the myocardium injured by a variety of pathological conditions. However, CPC may not survive the harsh, inflammatory microenvironment of damaged myocardium in which oxidative stress and pro-apoptotic factors are abundant. P53 acts as a negative cell cycle regulator and its expression may lead to cytostasis. Insulin-like growth factor (IGF-1) stimulates cell cycle re-entry. The PPARγ coactivator (PGC) serves as a muster regulator of mitochondria function. This study examined whether IGF-1 prevents oxidative stress-induced CPC mitochondrial dysfunction and cell cycle arrest via p53/PGC pathway.
Methods and Results: CPC incubated in the oxidative stress agent, hydrogen peroxide (H2O2, 150 μ M), resulted in increased p53 mRNA expression (2.9 ± 0.6 fold at 24 h, p<0.05, assessed by real-time PCR). H2O2 decreased mRNA expression of PGC, a target of p53 and a mitochondrial regulator. H2O2 also decreased mitochondrial biogenesis (indicated by mtDNA copy number), mitochondrial mass (assessed by Mitotracker Red) and energy production (ATP level). H2O2-induced cell cycle arrest was determined by analysis of DNA synthesis (BrdU assay) and cytokinesis (Calcein-AM fluorescence intensity). BrdU incorporation and Calcein-AM fluorescence intensity remained constant during at 72-h incubation. IGF-1 dose-dependently blocked H2O2 induced mitochondrial potential changes and cell cycle arrest. The IGF-1’s effects were attenuated by IGF-1 receptor neutralizing antibody and by PI3 kinase inhibitor (LY294002), but not by MAP kinase inhibitor (PD98059). IGF-1 also decreased p53 but increased PGC expression. Furthermore, silencing PGC using a small interference RNA (siRNA-PGC) could block IGF-1’s effects on mitochondrial function and cell cycle reentry. The control, non-targeting scrambled siRNA, did not have such blocking effects.
Conclusion: IGF-1 regulates the p53/PGC pathway and inhibits H2O2-induced mitochondrial dysfunction and cell cycle arrest. Our findings provide a new paradigm for the biological effects of IGF-1 on CPC cell cycle re-entry under oxidative stress, and suggest that employing IGF-1 treated CPC may be a useful strategy for repair of injured cardiovascular tissues.
- © 2012 by American Heart Association, Inc.