title: 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.
authors.affiliation: Interdisciplinary Stem Cell Institute.
authors.forename: Victoria
authors.initials: V
authors.lastname: Florea
authors.affiliation: Interdisciplinary Stem Cell Institute.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Majid
authors.affiliation: Interdisciplinary Stem Cell Institute, Departments of Molecular and Cellular Pharmacology.
authors.forename: Rosemeire M
authors.initials: RM
authors.lastname: Kanashiro-Takeuchi
authors.affiliation: Interdisciplinary Stem Cell Institute, Pathology, and Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Cai
authors.affiliation: Interdisciplinary Stem Cell Institute, Pathology, and Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Interdisciplinary Stem Cell Institute, Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125 Medicine, Divisions of Hematology/Oncology and crodrigues@med.miami.edu andrew.schally@va.gov.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Interdisciplinary Stem Cell Institute, Departments of Molecular and Cellular Pharmacology, Medicine, Divisions of Cardiology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.affiliation: Interdisciplinary Stem Cell Institute, Departments of Molecular and Cellular Pharmacology, crodrigues@med.miami.edu andrew.schally@va.gov.
authors.forename: Claudia O
authors.initials: CO
authors.lastname: Rodrigues
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
chemical_list: C420262:JI-38; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C060276:MR 356; D013007:Growth Hormone-Releasing Hormone; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000527:Alprostadil; C048250:somatotropin releasing hormone receptor
keywords: agonists; cardiac stem cells; cell proliferation; cell survival; growth hormone-releasing hormone