This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 110/4/444    most recent 01.CIR.0000136025.96811.76v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nagata, D. Articles by Hirata, Y. Search for Related Content PubMed PubMed Citation Articles by Nagata, D. Articles by Hirata, Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB HYDROGEN PEROXIDE Related Collections Mechanism of atherosclerosis/growth factors ACE/Angiotension receptors Cell signalling/signal transduction Smooth muscle proliferation and differentiation

(Circulation. 2004;110:444-451.)
© 2004 American Heart Association, Inc.

Original Articles

AMP-Activated Protein Kinase Inhibits Angiotensin II–Stimulated Vascular Smooth Muscle Cell Proliferation

Daisuke Nagata, MD, PhD; Ryo Takeda, MD; Masataka Sata, MD, PhD; Hiroshi Satonaka, MD; Etsu Suzuki, MD, PhD; Tetsuo Nagano, PhD; Yasunobu Hirata, MD, PhD

From the Department of Internal Medicine, Graduate School of Medicine (D.N., R.T., M.S., H.S., E.S., Y.H.), and Graduate School of Pharmaceutical Sciences (T.N.), University of Tokyo, Tokyo, Japan.

Correspondence to Yasunobu Hirata, MD, PhD, Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail hiratay-tky{at}umin.ac.jp

Received October 21, 2003; de novo received January 26, 2004; revision received April 1, 2004; accepted April 5, 2004.

Background— AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that works as a metabolic sensor of cellular ATP levels. Here, we investigated whether AMPK signaling has a role in the regulation of the angiotensin II (Ang II)-induced proliferation signal in rat vascular smooth muscle cells (VSMCs).

Methods and Results— Aminoimidazole-4-carboxamide-1-ß-ribofuranoside (AICAR) activated AMPK in rat VSMCs and inhibited Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation but not that of p38 MAPK or Akt/PKB. Although Ang II activated AMPK, this activation was significantly inhibited by catalase, N-acetylcysteine, and diphenyleneiodonium chloride, an NADPH oxidase inhibitor. Moreover, the observation that AMPK was activated by H₂O₂ suggests that AMPK is redox sensitive. The Ang II type 1 receptor antagonist valsartan but not the Ang II type 2 receptor antagonist PD123319 significantly inhibited Ang II-induced AMPK activation, suggesting that Ang II-induced AMPK activation was Ang II type 1 receptor dependent. Whereas ³H-thymidine incorporation by VSMCs treated with Ang II was significantly inhibited when the cells were pretreated with 1 mmol/L AICAR, the inhibition of AMPK by dominant-negative AMPK overexpression augmented Ang II-induced cell proliferation. Subcutaneous injection of AICAR (1 mg/g body weight per day) for 2 weeks suppressed neointimal formation after transluminal mechanical injury of the rat femoral artery.

Conclusions— Our findings indicate that Ang II-induced AMPK activation is synchronized with extracellular signal-regulated kinase signaling and that AMPK works as an inhibitor of the Ang II proliferative pathway. AMPK signaling might serve as a new therapeutic target of vascular remodeling in cardiovascular diseases.

Key Words: atherosclerosis • angiotensin • muscle, smooth • free radicals • signal transduction

This article has been cited by other articles:

				B.-K. Son, M. Akishita, K. Iijima, K. Kozaki, K. Maemura, M. Eto, and Y. Ouchi Adiponectin Antagonizes Stimulatory Effect of Tumor Necrosis Factor-{alpha} on Vascular Smooth Muscle Cell Calcification: Regulation of Growth Arrest-Specific Gene 6-Mediated Survival Pathway by Adenosine 5'-Monophosphate-Activated Protein Kinase Endocrinology, April 1, 2008; 149(4): 1646 - 1653. [Abstract] [Full Text] [PDF]

				M. Zhang, Y. Dong, J. Xu, Z. Xie, Y. Wu, P. Song, M. Guzman, J. Wu, and M.-H. Zou Thromboxane Receptor Activates the AMP-Activated Protein Kinase in Vascular Smooth Muscle Cells via Hydrogen Peroxide Circ. Res., February 15, 2008; 102(3): 328 - 337. [Abstract] [Full Text] [PDF]

				L. H. Young AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Circulation, February 12, 2008; 117(6): 832 - 840. [Full Text] [PDF]

				G. Ceolotto, A. Gallo, I. Papparella, L. Franco, E. Murphy, E. Iori, E. Pagnin, G. P. Fadini, M. Albiero, A. Semplicini, et al. Rosiglitazone Reduces Glucose-Induced Oxidative Stress Mediated by NAD(P)H Oxidase via AMPK-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2627 - 2633. [Abstract] [Full Text] [PDF]

				B. Burstein, X.-Y. Qi, Y.-H. Yeh, A. Calderone, and S. Nattel Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling Cardiovasc Res, December 1, 2007; 76(3): 442 - 452. [Abstract] [Full Text] [PDF]

				G. Wen, J. Wessel, W. Zhou, G. B. Ehret, F. Rao, M. Stridsberg, S. K. Mahata, P. M. Gent, M. Das, R. S. Cooper, et al. An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension Hum. Mol. Genet., July 15, 2007; 16(14): 1752 - 1764. [Abstract] [Full Text] [PDF]

				P. B. Bokko, L. Francione, E. Bandala-Sanchez, A. U. Ahmed, S. J. Annesley, X. Huang, T. Khurana, A. R. Kimmel, and P. R. Fisher Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling Mol. Biol. Cell, May 1, 2007; 18(5): 1874 - 1886. [Abstract] [Full Text] [PDF]

				A. Katz Modulation of glucose transport in skeletal muscle by reactive oxygen species J Appl Physiol, April 1, 2007; 102(4): 1671 - 1676. [Abstract] [Full Text] [PDF]

				A. M. Evans AMP-activated protein kinase underpins hypoxic pulmonary vasoconstriction and carotid body excitation by hypoxia in mammals Exp Physiol, September 1, 2006; 91(5): 821 - 827. [Abstract] [Full Text] [PDF]

				M. E. Sandstrom, S.-J. Zhang, J. Bruton, J. P. Silva, M. B. Reid, H. Westerblad, and A. Katz Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle J. Physiol., August 15, 2006; 575(1): 251 - 262. [Abstract] [Full Text] [PDF]

				H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]

				M. Quintero, S. L. Colombo, A. Godfrey, and S. Moncada Mitochondria as signaling organelles in the vascular endothelium PNAS, April 4, 2006; 103(14): 5379 - 5384. [Abstract] [Full Text] [PDF]

				D. S. Hutchinson and T. Bengtsson AMP-Activated Protein Kinase Activation by Adrenoceptors in L6 Skeletal Muscle Cells: Mediation by {alpha}1-Adrenoceptors Causing Glucose Uptake Diabetes, March 1, 2006; 55(3): 682 - 690. [Abstract] [Full Text] [PDF]

				Z. Goldberger and R. Lampert Implantable Cardioverter-Defibrillators: Expanding Indications and Technologies JAMA, February 15, 2006; 295(7): 809 - 818. [Abstract] [Full Text] [PDF]

				S. Han and J. Roman Rosiglitazone suppresses human lung carcinoma cell growth through PPAR{gamma}-dependent and PPAR{gamma}-independent signal pathways. Mol. Cancer Ther., February 1, 2006; 5(2): 430 - 437. [Abstract] [Full Text] [PDF]

				Y. Hattori, K. Akimoto, T. Nishikimi, H. Matsuoka, and K. Kasai Activation of AMP-Activated Protein Kinase Enhances Angiotensin II-Induced Proliferation in Cardiac Fibroblasts Hypertension, February 1, 2006; 47(2): 265 - 270. [Abstract] [Full Text] [PDF]

				S K Richards, L E Parton, I Leclerc, G A Rutter, and R M Smith Over-expression of AMP-activated protein kinase impairs pancreatic {beta}-cell function in vivo J. Endocrinol., November 1, 2005; 187(2): 225 - 235. [Abstract] [Full Text] [PDF]

				M. Igata, H. Motoshima, K. Tsuruzoe, K. Kojima, T. Matsumura, T. Kondo, T. Taguchi, K. Nakamaru, M. Yano, D. Kukidome, et al. Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression Circ. Res., October 14, 2005; 97(8): 837 - 844. [Abstract] [Full Text] [PDF]

				L. Tosca, P. Froment, P. Solnais, P. Ferre, F. Foufelle, and J. Dupont Adenosine 5'-Monophosphate-Activated Protein Kinase Regulates Progesterone Secretion in Rat Granulosa Cells Endocrinology, October 1, 2005; 146(10): 4500 - 4513. [Abstract] [Full Text] [PDF]

				K.-G. Shyu, Y.-M. Chao, B.-W. Wang, and P. Kuan Regulation of Discoidin Domain Receptor 2 by Cyclic Mechanical Stretch in Cultured Rat Vascular Smooth Muscle Cells Hypertension, September 1, 2005; 46(3): 614 - 621. [Abstract] [Full Text] [PDF]

				R. Pullmann Jr., M. Juhaszova, I. L. de Silanes, T. Kawai, K. Mazan-Mamczarz, M. K. Halushka, and M. Gorospe Enhanced Proliferation of Cultured Human Vascular Smooth Muscle Cells Linked to Increased Function of RNA-binding Protein HuR J. Biol. Chem., June 17, 2005; 280(24): 22819 - 22826. [Abstract] [Full Text] [PDF]

				F. Labarthe, M. Khairallah, B. Bouchard, W. C. Stanley, and C. Des Rosiers Fatty acid oxidation and its impact on response of spontaneously hypertensive rat hearts to an adrenergic stress: benefits of a medium-chain fatty acid Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1425 - H1436. [Abstract] [Full Text] [PDF]