| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 3, 2003
Accepted on September 2, 2003
1 Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N Torrey Pines Road, La Jolla, CA, U. S. A. From the Department of Medical Physiology , Institute of Medical Biology, Faculty of Medicine, University of Tromsø, Norway. From The Institute Of Child Health University College London, 30 Guilford Street, London, WC1N 1EH.
* To whom correspondence should be addressed. E-mail: vale{at}salk.edu.
Corticotrophin releasing factor (CRF) receptor type 2 
(CRFR2) is expressed in the heart. Urocortin-I (Ucn-I) activation of CRFR2 is cardioprotective against ischemic reperfusion (I/R) injury by stimulation of the extracellular receptor kinases (ERK1/2) p-42, 44. However, by binding CRF receptor type 1 (CRFR1), Ucn-I can also activate the hypothalamic stress axis (HPA). Urocortin-II (Ucn-II)/Stresscopin Related Peptide and Urocortin-III (Ucn-III)/Stresscopin are two new members of the CRF/Ucn-I gene family and are selective for CRFR2. We propose that CRFR2 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 CRFR2, resulting in ERK1/2-p42, 44 phosphorylation and cAMP stimulation. Phosphorylation of ERK1/2-p42, 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 due to their potent cardioprotective effects in the murine heart and their minimal impact on the HPA axis. We emphasize an important endogenous cardioprotective role for CRFR2 in the murine heart.
This article has been cited by other articles:
 |
|
 |
|
  T. Angelone, A. M. Quintieri, B. K. Brar, P. T. Limchaiyawat, B. Tota, S. K. Mahata, and M. C. Cerra The Antihypertensive Chromogranin A Peptide Catestatin Acts as a Novel Endocrine/Paracrine Modulator of Cardiac Inotropism and Lusitropism Endocrinology, October 1, 2008; 149(10): 4780 - 4793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mazza, A. Gattuso, C. Mannarino, B. K. Brar, S. F. Barbieri, B. Tota, and S. K. Mahata Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H113 - H122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Davis, C. J. Pemberton, T. G. Yandle, S. F. Fisher, J. G. Lainchbury, C. M. Frampton, M. T. Rademaker, and M. Richards Urocortin 2 infusion in human heart failure Eur. Heart J., November 1, 2007; 28(21): 2589 - 2597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Townsend, S. M. Davidson, S. J. Clarke, I. Khaliulin, C. J. Carroll, T. M. Scarabelli, R. A. Knight, A. Stephanou, D. S. Latchman, and A. P. Halestrap Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H928 - H938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Wu, P.-q. Yuan, L. Wang, Y. L. Peng, C.-Y. Chen, and Y. Tache Identification and Characterization of Multiple Corticotropin-Releasing Factor Type 2 Receptor Isoforms in the Rat Esophagus Endocrinology, April 1, 2007; 148(4): 1675 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Davis, C. J. Pemberton, T. G. Yandle, S. F. Fisher, J. G. Lainchbury, C. M. Frampton, M. T. Rademaker, and A. M. Richards Urocortin 2 Infusion in Healthy Humans: Hemodynamic, Neurohormonal, and Renal Responses J. Am. Coll. Cardiol., January 30, 2007; 49(4): 461 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Negro, B. K. Brar, Y. Gu, K. L. Peterson, W. Vale, and K.-F. Lee erbB2 is required for G protein-coupled receptor signaling in the heart PNAS, October 24, 2006; 103(43): 15889 - 15893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. W. Hillhouse and D. K. Grammatopoulos The Molecular Mechanisms Underlying the Regulation of the Biological Activity of Corticotropin-Releasing Hormone Receptors: Implications for Physiology and Pathophysiology Endocr. Rev., May 1, 2006; 27(3): 260 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Solinas, S. Summermatter, D. Mainieri, M. Gubler, J. P. Montani, J. Seydoux, S. R. Smith, and A. G. Dulloo Corticotropin-Releasing Hormone Directly Stimulates Thermogenesis in Skeletal Muscle Possibly through Substrate Cycling between de Novo Lipogenesis and Lipid Oxidation Endocrinology, January 1, 2006; 147(1): 31 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Rademaker, C. J. Charles, E. A. Espiner, C. M. Frampton, J. G. Lainchbury, and A. M. Richards Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure Eur. Heart J., October 1, 2005; 26(19): 2046 - 2054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chen, M. Perrin, B. Brar, C. Li, P. Jamieson, M. DiGruccio, K. Lewis, and W. Vale Mouse Corticotropin-Releasing Factor Receptor Type 2{alpha} Gene: Isolation, Distribution, Pharmacological Characterization and Regulation by Stress and Glucocorticoids Mol. Endocrinol., February 1, 2005; 19(2): 441 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Guillemin Hypothalamic hormones a.k.a. hypothalamic releasing factors J. Endocrinol., January 1, 2005; 184(1): 11 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Takahashi, K. Totsune, O. Murakami, M. Saruta, M. Nakabayashi, T. Suzuki, H. Sasano, and S. Shibahara Expression of Urocortin III/Stresscopin in Human Heart and Kidney J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1897 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Woodcock Unc-II and Unc-III Are Cardioprotective against Ischemia Reperfusion Injury: An Essential Endogenous Cardioprotective Role for CRFR2 in the Murine Heart Endocrinology, January 1, 2004; 145(1): 21 - 23. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
