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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 48; pp. 17260 - 17265
• Main Authors: Florea, Victoria, Majid, Sonia S., Kanashiro-Takeuchi, Rosemeire M., Cai, Ren-Zhi, Block, Norman L., Schally, Andrew V., Hare, Joshua M., Rodrigues, Claudia O.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.12.2014; National Acad Sciences
• Subjects: Agonists; Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Animals; Biological Sciences; Cell division; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Flow Cytometry; Gene expression; Growth Hormone-Releasing Hormone - analogs & derivatives; Growth Hormone-Releasing Hormone - pharmacology; Growth hormones; Heart; HeLa Cells; Hormones; Humans; Hydrogen peroxide; MCF-7 Cells; Mesenchymal stem cells; Mice; Myocardial infarction; Myocardium - cytology; Preconditioning; Progenitor cells; Proto-Oncogene Proteins c-akt - metabolism; Rats; Receptors, Neuropeptide - agonists; Receptors, Neuropeptide - genetics; Receptors, Neuropeptide - metabolism; Receptors, Pituitary Hormone-Regulating Hormone - agonists; Receptors, Pituitary Hormone-Regulating Hormone - genetics; Receptors, Pituitary Hormone-Regulating Hormone - metabolism; Signal Transduction - drug effects; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Survival analysis; Swine; T cell receptors; Transplantation; agonists; cell survival; cardiac stem cells; growth hormone-releasing hormone; cell proliferation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1420375111

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.