Abstract 19258: Cytoprotective Effect of Growth Hormone Releasing Hormone Agonists in Cardiac Stem Cells
Introduction and hypothesis: Our group has previously shown that agonists of growth hormone releasing hormone receptor (GHRHR) improve cardiac performance in heart failure models and reverse remodeling. This effect was associated with an increase in the number of c-kit+ cardiac stem cells (CSC), suggesting that this agonist might have an effect on these cells.
Methods and Results: We investigated the expression of GHRHR in CSC of different species by flow cytometry analysis. GHRH-R is expressed in 96-98% of CSC isolated from mouse, rat and pig. Results were compared to GHRHR expression in HeLa (positive control) and MCF7 and T47D cell lines (negative control). To determine if GHRHR activation can improve CSC self-renewal, we tested the effect of GHRH agonists on porcine CSC proliferation. The rate of cell division was increased 2-fold with JI38 (GHRHR agonist) treatment (3.4 ± 0.7) vs. vehicle control (1.7 ± 0.2) (p<0.05). Pre-treatment of CSC with GHRHR antagonist, MIA-602, showed a trend toward reversal of the agonistic effect of JI38 on proliferation rates (2.2 ± 0.6). These studies were further extended to other GHRHR agonists. JI38, MR356 and MR409 showed significant increases in CSC proliferation relative to vehicle control, by 20 ± 5.7%, 37 ± 8.5% and 36 ± 12.2%, respectively (p<0.05). The protective effect of JI38 on porcine CSC survival was determined under oxidative stress generated by hydrogen peroxide exposure. Pre-treatment of CSC with JI38 prior to peroxide exposure significantly reduced cell death by 33 ± 2.2% (p<0.02). Similar effects were observed for MR356, which decreased cell death by 12 ± 8.6% (p<0.03). Furthermore, we found that the effect of GHRHR-A on CSC proliferation was completely reversed by inhibitors of the ERK, PI3K and Akt pathways (p<0.05).
Conclusion: These findings show for the first time the expression of GHRHR in CSC. GHRHR agonists promote CSC proliferation and enhance survival. GHRHR-A effects on CSC proliferation are mediated through activation of ERK, PI3K and AKT pathways. Activation of GHRHR signaling pathways represents a novel therapeutic approach to protect and stimulate endogenous CSC population thus promoting cardiac repair.
Author Disclosures: V. Florea: None. S.S. Majid: None. R.M. Kanashiro-Takeuchi: None. N.L. Block: Ownership Interest; Modest; Biscayne Pharmaceuticals, Inc. A.V. Schally: Research Grant; Modest; Ferring. Honoraria; Modest; Ferring. Ownership Interest; Modest; Biscayne Pharmaceuticals, Inc. J.M. Hare: Employment; Modest; Vestion. Ownership Interest; Modest; Biscayne. Ownership Interest; Significant; Vestion Inc. C.O. Rodrigues: None.
- © 2014 by American Heart Association, Inc.