Published online before print December 22, 2003, doi: 10.1161/01.CIR.0000109214.30211.7C
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;109:242-248.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway
From the Department of Biochemistry (H.O., I.O., J.H., K.M., K.K.), National Cardiovascular Center Research Institute, Osaka, Japan; Department of Internal Medicine (N.N., T.I.) and Department of Pathology (Y.T., H.I.-U., C.Y.), National Cardiovascular Center, Osaka, Japan; and Department of Cardiovascular Surgery (S.M., K.T.) and Department of Pathology and Biology of Diseases (S.T.), Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Correspondence to Noritoshi Nagaya, MD, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail nagayann{at}hsp.ncvc.go.jp
Received January 27, 2003; de novo received August 11, 2003; accepted September 22, 2003.
Background— Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown.
Methods and Results— Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28±4% to 16±1%, P<0.01), left ventricular end-diastolic pressure (19±2 to 8±2 mm Hg, P<0.05), and myocardial apoptotic death (19±2% to 9±4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion.
Conclusions— Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.
Key Words: peptides • reperfusion • apoptosis • myocardial infarction • hemodynamics
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
|
|
B. Yanagawa, M. Kataoka, S. Ohnishi, M. Kodama, K. Tanaka, Y. Miyahara, H. Ishibashi-Ueda, Y. Aizawa, K. Kangawa, and N. Nagaya Infusion of adrenomedullin improves acute myocarditis via attenuation of myocardial inflammation and edema Cardiovasc Res, October 1, 2007; 76(1): 110 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Itoh, H. Obata, S. Murakami, K. Hamada, K. Kangawa, H. Kimura, and N. Nagaya Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L446 - L452. [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]
|
|
|
|
 |
|
 J. Liu, T. Shimosawa, H. Matsui, F. Meng, S. C. Supowit, D. J. DiPette, K. Ando, and T. Fujita Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1714 - H1721. [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]
|
|
|
|
 |
|
 A. Kenessey and K. Ojamaa Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70S6K Pathways J. Biol. Chem., July 28, 2006; 281(30): 20666 - 20672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Uzan, H.-K. Ea, J.-M. Launay, J.-M. Garel, R. Champy, M. Cressent, and F. Liote A Critical Role for Adrenomedullin-Calcitonin Receptor-Like Receptor in Regulating Rheumatoid Fibroblast-Like Synoviocyte Apoptosis J. Immunol., May 1, 2006; 176(9): 5548 - 5558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bae and L. Zhang Gender Differences in Cardioprotection against Ischemia/Reperfusion Injury in Adult Rat Hearts: Focus on Akt and Protein Kinase C Signaling J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1125 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Nagaya, K. Kangawa, T. Itoh, T. Iwase, S. Murakami, Y. Miyahara, T. Fujii, M. Uematsu, H. Ohgushi, M. Yamagishi, et al. Transplantation of Mesenchymal Stem Cells Improves Cardiac Function in a Rat Model of Dilated Cardiomyopathy Circulation, August 23, 2005; 112(8): 1128 - 1135. [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]
|
|
|
|
 |
|
 K. Hanabusa, N. Nagaya, T. Iwase, T. Itoh, S. Murakami, Y. Shimizu, W. Taki, K. Miyatake, and K. Kangawa Adrenomedullin Enhances Therapeutic Potency of Mesenchymal Stem Cells After Experimental Stroke in Rats Stroke, April 1, 2005; 36(4): 853 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Fujii, N. Nagaya, T. Iwase, S. Murakami, Y. Miyahara, K. Nishigami, H. Ishibashi-Ueda, M. Shirai, T. Itoh, K. Ishino, et al. Adrenomedullin enhances therapeutic potency of bone marrow transplantation for myocardial infarction in rats Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1444 - H1450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Iwase, N. Nagaya, T. Fujii, T. Itoh, H. Ishibashi-Ueda, M. Yamagishi, K. Miyatake, T. Matsumoto, S. Kitamura, and K. Kangawa Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia Circulation, January 25, 2005; 111(3): 356 - 362. [Abstract] [Full Text] [PDF]
|
|