title: Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart.
abstract: Corticotropin-releasing factor (CRF) receptor type 2beta (CRFR2beta) is expressed in the heart. Urocortin (Ucn)-I activation of CRFR2beta is cardioprotective against ischemic reperfusion (I/R) injury by stimulation of the ERKs1/2 p42, 44. However, by binding CRF receptor type 1, Ucn-I can also activate the hypothalamic stress axis. Ucn-II/stresscopin related peptide and Ucn-III/stresscopin are two new members of the CRF/Ucn-I gene family and are selective for CRFR2beta. We propose that CRFR2beta selective Ucn-II or Ucn-III will protect cardiomyocytes and the ex vivo Langendorff perfused rat heart from I/R injury by activation of ERK1/2-p42, 44. Ucn-II is expressed in mouse cardiomyocytes, and Ucn-II or Ucn-III can bind to CRFR2beta, resulting in ERK1/2-p42, p-44 phosphorylation and cAMP stimulation. Phosphorylation of ERK1/2-p42, p-44 is regulated by the Ras/Raf-1 kinase pathway, independent of adenylate cyclase and, therefore, cAMP activation. Ucn-II and Ucn-III protect cardiomyocytes from I/R injury and reduce the percentage of infarct size:risk ratio in Langendorff perfused rat hearts exposed to regional I/R (P<0.001). The CRFR2 selective antagonist astressin2-B and an ERK1/2-p42, 44 inhibitor abolish the cardioprotective actions of Ucn-II and Ucn-III in reperfusion. Cardiomyocytes isolated from CRFR2-null mice are less resistant to I/R injury, compared with wild-type cardiomyocytes. We propose the use of CRFR2 selective agonists, Ucn-II and Ucn-III, to treat ischemic heart disease because of their potent cardioprotective effects in the murine heart and their minimal impact on the hypothalamic stress axis. We emphasize an important endogenous cardioprotective role for CRFR2beta in the murine heart.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA.
authors.forename: Bhawanjit K
authors.initials: BK
authors.lastname: Brar
authors.forename: Anne K
authors.initials: AK
authors.lastname: Jonassen
authors.forename: Elena M
authors.initials: EM
authors.lastname: Egorina
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.forename: Alejandra
authors.initials: A
authors.lastname: Negro
authors.forename: Marilyn H
authors.initials: MH
authors.lastname: Perrin
authors.forename: Ole D
authors.initials: OD
authors.lastname: Mjøs
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Kuo-Fen
authors.initials: KF
authors.lastname: Lee
authors.forename: Wylie
authors.initials: W
authors.lastname: Vale
mesh_terms: D000367:Age Factors; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D054832:Urocortins
chemical_list: C101531:CRF receptor type 2; D002316:Cardiotonic Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C518358:urocortin 2, mouse; D003346:Corticotropin-Releasing Hormone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases