Abstract 14474: Hedgehog Interacting Protein Controls Age-Dependent Angiogenic Activity in Human Cardiac Progenitor Cells Through Insulin-Like Growth Factor-1 Receptor Signaling
Background- The rate of human myocyte turnover declines with age by loss of intrinsic cardiogenic potency of cardiac progenitor cells (CPCs). Although those myocytes are fed by vessels, angoigenic activity of CPCs remains to be elucidated. So we clarify angiogenic potency of CPCs and the molecular mechanisms involved in angiogenesis.
Methods and Results- Human CPCs were isolated from myocardial specimens of 90 patients and classified into 2 groups (neonate and infant) along with age. Global gene expression analysis, quantitative RT-PCR, and differentiation potential were examined. RNA interference using exogenous short interference RNAs was performed to verify the genetic function. Tube formation analysis showed that infant CPCs had higher angiogenic activity with the secretion of various growth factors, whereas insulin-like growth factor-1 receptor (IGF1R) showed an augmented expression in neonates when myocyte turnover was prominent. Gene expression analysis showed 3 candidate genes include hedgehog-interacting protein (HHIP), heparin-binding epidermal growth factor (HB-EGF), and homeodomain-zinc finger protein ZFHX4 were significantly upregulated in neonatal CPCs. Knockdown of IGF1R in neonatal CPCs exhibited an enhanced angiogenic activity compared with control CPCs. This observation was addressed by a significant decrease in HHIP expression, whereas the levels of HB-EGF and ZFHX4 remained unchanged. To investigate whether HHIP might be the direct targets for controlling the angiogenesis, endogenous HHIP was interfered in CPCs. Knockdown of HHIP significantly increased the angiogenic activity similar to that found in CPCs treated by IGF1R inhibition.
Conclusions- Our results suggest a functional significance of IGF1R-mediated physiological alteration of human CPC differentiation potential. HHIP controls age-dependent angiogenic activity in human cardiac progenitor cells under IGF pathway, and may be a therapeutic target to modulate human CPC in the development of new therapies for heart failure.
- © 2012 by American Heart Association, Inc.