Published online before print June 21, 2001, doi: 10.1161/hh1301.092498
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2001 American Heart Association, Inc.
Integrative Physiology |
Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt–Dependent Pathway in Rat Aorta
From the Department of Urology (H.N., N.M., T.K.) and the Second Department of Internal Medicine (E.S., D.N., H.S., M.S., A.G., Y.H.), Faculty of Medicine, University of Tokyo, Japan; Division of Cardiovascular Research (K.W.), St. Elizabeth’s Medical Center of Boston, Boston, Mass; and National Cardiovascular Center Research Institute (K.K., H.M.), Fujishirodai, Japan.
Correspondence to Etsu Suzuki, MD, PhD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail suzuki-2im{at}h.u-tokyo.ac.jp
Abstract
Abstract—To study the mechanisms by which adrenomedullin (AM) induces endothelium-dependent vasorelaxation, we examined whether AM-induced endothelium-dependent vasodilation was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway in rat aorta, because it was recently reported that PI3K/Akt was implicated in the activation of endothelial NO synthase. AM-induced vasorelaxation in thoracic aorta with intact endothelium was inhibited by pretreatment with PI3K inhibitors to the same level as that in endothelium-denuded aorta. AM elicited Akt phosphorylation in a time- and dose-dependent manner. AM-induced Akt phosphorylation was inhibited by pretreatment with a calmodulin-dependent protein kinase inhibitor as well as with PI3K inhibitors. When an adenovirus construct expressing a dominant-negative Akt mutant (Ad/dnAkt) was injected into abdominal aortas so that the mutant was expressed predominantly in the endothelium layer, AM-induced vasodilation was diminished to the same level as that in endothelium-denuded aortas. Finally, AM-induced cGMP production, which was used as an indicator for NO production, was suppressed by PI3K inhibition or by Ad/dnAkt infection into the endothelium. These results suggested that AM induced Akt activation in the endothelium via the Ca2+/calmodulin-dependent pathway and that this was implicated in the production of NO, which in turn induced endothelium-dependent vasodilation in rat aorta.
Key Words: adrenomedullin • phosphatidylinositol 3-kinase • Akt • nitric oxide • gene transfer
This article has been cited by other articles:
 |
|
 |
|
  B. Temmesfeld-Wollbruck, B. Brell, C. zu Dohna, M. Dorenberg, A. C. Hocke, H. Martens, J. Klar, N. Suttorp, and S. Hippenstiel Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G43 - G51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Geambasu and T. L. Krukoff Adrenomedullin acts in the lateral parabrachial nucleus to increase arterial blood pressure through mechanisms mediated by glutamate and nitric oxide Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R38 - R44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nishida, T. Sato, M. Miyazaki, and H. Nakaya Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels Cardiovasc Res, January 15, 2008; 77(2): 398 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ertmer, A. Morelli, S. Rehberg, M. Lange, C. Hucklenbruch, H. Van Aken, M. Booke, and M. Westphal Exogenous adrenomedullin prevents and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxaemia Br. J. Anaesth., December 1, 2007; 99(6): 830 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Gomez, M. J. Moreno, A. Iglesias, P. X. Coral, and A. Hernandez Endothelin 1, its Endothelin Type A Receptor, Connective Tissue Growth Factor, Platelet-Derived Growth Factor, and Adrenomedullin Expression in Lungs of Pulmonary Hypertensive and Nonhypertensive Chickens Poult. Sci., May 1, 2007; 86(5): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ma, J.-G. Chabot, and R. Quirion A role for adrenomedullin as a pain-related peptide in the rat PNAS, October 24, 2006; 103(43): 16027 - 16032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Ross and C. Yallampalli Endothelium-Independent Relaxation by Adrenomedullin in Pregnant Rat Mesenteric Artery: Role of cAMP-Dependent Protein Kinase A and Calcium-Activated Potassium Channels J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1269 - 1275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.W. Tam, K. Husmann, N.C. Clark, J.E. Clark, Z. Lazar, L.M. Ittner, J. Gotz, G. Douglas, A.D. Grant, D. Sugden, et al. Enhanced Vascular Responses to Adrenomedullin in Mice Overexpressing Receptor-Activity-Modifying Protein 2 Circ. Res., February 3, 2006; 98(2): 262 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Takeda, H. Nishimatsu, E. Suzuki, H. Satonaka, D. Nagata, S. Oba, M. Sata, M. Takahashi, Y. Yamamoto, Y. Terauchi, et al. Ghrelin Improves Renal Function in Mice with Ischemic Acute Renal Failure J. Am. Soc. Nephrol., January 1, 2006; 17(1): 113 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kato, T. Tsuruda, T. Kita, K. Kitamura, and T. Eto Adrenomedullin: A Protective Factor for Blood Vessels Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2480 - 2487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nagaya, H. Mori, S. Murakami, K. Kangawa, and S. Kitamura Adrenomedullin: angiogenesis and gene therapy Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1432 - R1437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xu and T. L. Krukoff Adrenomedullin Stimulates Nitric Oxide Release from SK-N-SH Human Neuroblastoma Cells by Modulating Intracellular Calcium Mobilization Endocrinology, May 1, 2005; 146(5): 2295 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Li and K. U. Malik Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca2+-dependent phospholipase A2 Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2306 - H2316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nishimatsu, E. Suzuki, H. Satonaka, R. Takeda, M. Omata, T. Fujita, R. Nagai, T. Kitamura, and Y. Hirata Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1770 - H1776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Nakamura, J. Kato, K. Kitamura, H. Onitsuka, T. Imamura, Y. Cao, K. Marutsuka, Y. Asada, K. Kangawa, and T. Eto Adrenomedullin Administration Immediately After Myocardial Infarction Ameliorates Progression of Heart Failure in Rats Circulation, July 27, 2004; 110(4): 426 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Brain and A. D. Grant Vascular Actions of Calcitonin Gene-Related Peptide and Adrenomedullin Physiol Rev, July 1, 2004; 84(3): 903 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsui, T. Shimosawa, K. Itakura, X. Guanqun, K. Ando, and T. Fujita Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia Circulation, May 11, 2004; 109(18): 2246 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tokunaga, N. Nagaya, M. Shirai, E. Tanaka, H. Ishibashi-Ueda, M. Harada-Shiba, M. Kanda, T. Ito, W. Shimizu, Y. Tabata, et al. Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia: Benefits of a Novel Nonviral Vector, Gelatin Circulation, February 3, 2004; 109(4): 526 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Okumura, N. Nagaya, T. Itoh, I. Okano, J. Hino, K. Mori, Y. Tsukamoto, H. Ishibashi-Ueda, S. Miwa, K. Tambara, et al. Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway Circulation, January 20, 2004; 109(2): 242 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Champion, T. J. Bivalacqua, R. L. Pierce, W. A. Murphy, D. H. Coy, A. L. Hyman, and P. J. Kadowitz Responses to human CGRP, ADM, and PAMP in human thymic arteries Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R531 - R537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Dobrzynski, D. Montanari, J. Agata, J. Zhu, J. Chao, and L. Chao Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1291 - E1298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhou, Z. F. Ba, I. H. Chaudry, and P. Wang Adrenomedullin binding protein-1 modulates vascular responsiveness to adrenomedullin in late sepsis Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R553 - R560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Shiojima and K. Walsh Role of Akt Signaling in Vascular Homeostasis and Angiogenesis Circ. Res., June 28, 2002; 90(12): 1243 - 1250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Scotland, M. Morales-Ruiz, Y. Chen, J. Yu, R. D. Rudic, D. Fulton, J.-P. Gratton, and W. C. Sessa Functional Reconstitution of Endothelial Nitric Oxide Synthase Reveals the Importance of Serine 1179 in Endothelium-Dependent Vasomotion Circ. Res., May 3, 2002; 90(8): 904 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fulton, J. Fontana, G. Sowa, J.-P. Gratton, M. Lin, K.-X. Li, B. Michell, B. E. Kemp, D. Rodman, and W. C. Sessa Localization of Endothelial Nitric-oxide Synthase Phosphorylated on Serine 1179 and Nitric Oxide in Golgi and Plasma Membrane Defines the Existence of Two Pools of Active Enzyme J. Biol. Chem., February 1, 2002; 277(6): 4277 - 4284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Scotland, M. Morales-Ruiz, Y. Chen, J. Yu, R. D. Rudic, D. Fulton, J.-P. Gratton, and W. C. Sessa Functional Reconstitution of Endothelial Nitric Oxide Synthase Reveals the Importance of Serine 1179 in Endothelium-Dependent Vasomotion Circ. Res., May 3, 2002; 90(8): 904 - 910. [Abstract] [Full Text] [PDF]
|
|