Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

Victoria Florea, Sonia S. Majid, Rosemeire M. Kanashiro-Takeuchi, Ren Zhi Cai, Norman L. Block, Andrew V. Schally, Joshua M. Hare, Claudia O. Rodrigues

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit+ cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit+ CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation.

Original languageEnglish (US)
Pages (from-to)17260-17265
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number48
DOIs
StatePublished - Dec 2 2014

    Fingerprint

Keywords

  • Agonists |
  • Cardiac stem cells |
  • Cell proliferation |
  • Cell survival
  • Growth hormone-releasing hormone |

ASJC Scopus subject areas

  • General

Cite this