Journal Article

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

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

2014

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 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 / heart failure / HeLa Cells / hormone receptors / Hormones / Humans / Hydrogen peroxide / islets of Langerhans / MCF-7 Cells / Mesenchymal stem cells / Mice / Myocardial infarction / myocardium / Myocardium - cytology / Oxidative stress / 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 / somatoliberin / Stem cells / Stem Cells - drug effects / Stem Cells - metabolism / Survival / Survival analysis / Swine / T cell receptors / therapeutics / Transplantation