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

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.cardiac stem cells | growth hormone-releasing hormone | agonists | cell proliferation | cell survival

cKit + cardiac progenitors of neural crest origin

“…Following the seminal description by Beltrami et al (16) of clusters of cKit cells in the postnatal mammalian heart, several laboratories, including ours, suggested that cKit marks CPs (16)(17)(18)(19), a finding that led to the clinical testing of these cells for heart repair (20). Recently, a straightforward genetic fate-mapping study showed that a relatively small proportion of murine myocardium is derived from cKit + CPs, leading to the conclusion that the cardiomyogenic capacity of cKit + CPs is functionally insignificant (21).…”

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

“…GHRH has been shown to induce proliferation of pituitary somatotroph cells; the pathway involving cAMP/protein kinase A is important in cells targeted by GHRH (22,23). It was also reported that GHRH(1-29)NH 2 and its agonists can activate mitogen-activated protein kinase (MAPK) in pituitary cells, porcine stem cells (15), and in cell lines overexpressing the GHRH receptor (24,25), whereas GHRH antagonists inhibit cAMP production and inactivate ERK and AKT kinases in cancer cells (26,27). However, the mechanism of GHRH and its agonists on pancreatic β cells has not yet been elucidated.…”

“…Hypothalamic growth hormone-releasing hormone (GHRH) stimulates production and release of GH from the pituitary gland, exerts some of its effects through the GH/IGF axis, and also directly affects extrapituitary cells expressing GHRH receptors by activating these receptors. GHRH receptor(s) have been detected in various tumor cells, stem cells, and other tissues including pancreatic β cells (12)(13)(14)(15)(16). Understanding the action of GHRH on its target cells is important for potential application in the use of synthetic GHRH analogs, with prolonged half-lives, which may provide a promising pharmacologic therapy in various fields.…”

“…The analogs, designated as "MR series," display higher endocrine potencies on in vivo GH release and greater binding affinity to GHRH receptor, compared with JI class GHRH analogs. Among these agonists, MR-356 and MR-409 exhibit the highest potency in activating myocardial repair in rats with induced myocardial infarction and efficiently stimulate selfrenewal and promote the survival of porcine cardiac stem cells (15).…”

Tadalafil, a Phosphodiesterase Inhibitor Protects Stem Cells over Longer Period Against Hypoxia/Reoxygenation Injury Through STAT3/PKG-I Signaling

“…Foresta et al reported that vardendafil promoted significant mobilization of endothelial progenitor cells in patients [22]. Recently, Hare and colleagues reported that PC of cardiac stem cells with agonists of growth hormone-releasing hormone receptor promoted their proliferation and survival [23]. Besides the direct effect of PDE inhibitors on stem cell survival, overexpression of PKG-I, an important mediator of protection, through adenoviral transduction also increases stem cell survival upon oxygen glucose deprivation as well as cardioprotection against myocardial infarction [24].…”