Browse > Article
http://dx.doi.org/10.4196/kjpp.2010.14.5.299

Losartan Inhibits Vascular Smooth Muscle Cell Proliferation through Activation of AMP-Activated Protein Kinase  

Kim, Jung-Eun (Department of Pharmacology, Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University)
Choi, Hyoung-Chul (Department of Pharmacology, Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.14, no.5, 2010 , pp. 299-304 More about this Journal
Abstract
Losartan is a selective angiotensin II (Ang II) type 1 ($AT_1$) receptor antagonist which inhibits vascular smooth muscle cells (VSMCs) contraction and proliferation. We hypothesized that losartan may prevent cell proliferation by activating AMP-activated protein kinase (AMPK) in VSMCs. VSMCs were treated with various concentrations of losartan. AMPK activation was measured by Western blot analysis and cell proliferation was measured by MTT assay and flowcytometry. Losartan dose- and time-dependently increased the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in VSMCs. Losartan also significantly decreased the Ang II- or 15% FBS-induced VSMC proliferation by inhibiting the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. Compound C, a specific inhibitor of AMPK, or AMPK siRNA blocked the losartan-induced inhibition of cell proliferation and the $G_0/G_1$ cell cycle arrest. These data suggest that losartan-induced AMPK activation might attenuate Ang II-induced VSMC proliferation through the inhibition of cell cycle progression.
Keywords
AMP-activated protein kinase (AMPK); Angiotensin II type 1 ($AT_1$) receptor antagonist; Losartan; Vascular smooth muscle cells (VSMCs); Proliferation;
Citations & Related Records

Times Cited By Web Of Science : 9  (Related Records In Web of Science)
Times Cited By SCOPUS : 5
연도 인용수 순위
1 Hardie DG. The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci. 2004;117:5479-5487.   DOI   ScienceOn
2 Igata M, Motoshima H, Tsuruzoe K, Kojima K, Matsumura T, Kondo T, Taguchi T, Nakamaru K, Yano M, Kukidome D, Matsumoto K, Toyonaga T, Asano T, Nishikawa T, Araki E. Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ Res. 2005;97:837-844.   DOI   ScienceOn
3 Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651-657.   DOI   ScienceOn
4 Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA, Kurtz TW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 2004;43:993-1002.   DOI   ScienceOn
5 Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003;42:76-81.   DOI   ScienceOn
6 Richey JM, Ader M, Moore D, Bergman RN. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am J Physiol. 1999;277:E920-E926.
7 Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes. 2006;55:2180-2191.   DOI   ScienceOn
8 Choi HC, Song P, Xie Z, Wu Y, Xu J, Zhang M, Dong Y, Wang S, Lau K, Zou MH. Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J Biol Chem. 2008;283:20186-20197.   DOI   ScienceOn
9 Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol. 2006;574:63-71.   DOI   ScienceOn
10 Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535.   DOI   ScienceOn
11 Fujimoto M, Masuzaki H, Tanaka T, Yasue S, Tomita T, Okazawa K, Fujikura J, Chusho H, Ebihara K, Hayashi T, Hosoda K, Nakao K. An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. FEBS Lett. 2004;576:492-497.   DOI   ScienceOn
12 Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Katagiri H, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Komuro I, Fujita T. Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension. 2002;40:872-879.   DOI   ScienceOn
13 Umeda M, Kanda T, Murakami M. Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats. Hypertens. Res. 2003;26:485-492.   DOI   ScienceOn
14 Henriksen EJ, Jacob S, Kinnick TR, Teachey MK, Krekler M. Selective angiotensin II receptor receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension. 2001;38:884-890.   DOI   ScienceOn
15 Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG 4th, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004;279:43940-43951.   DOI   ScienceOn
16 Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K, Froguel P, Nagai R, Kadowaki T. Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr Drug Targets Immune Endocr Metabol Disord. 2003;3:243-254.   DOI   ScienceOn
17 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288-1295.   DOI   ScienceOn
18 Nozawa Y, Matsuura N, Miyake H, Yamada S, Kimura R. Effects of TH-142177 on angiotensin II-induced proliferation, migration and intracellular signaling in vascular smooth muscle cells and on neointimal thickening after balloon injury. Life Sci. 1999;64:2061-2070.   DOI   ScienceOn
19 Nagata D, Takeda R, Sata M, Satonaka H, Suzuki E, Nagano T, Hirata Y. AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation. Circulation. 2004;110:444-451.   DOI   ScienceOn
20 Asmar R. Targeting effective blood pressure control with angiotensin receptor blockers. Int J Clin Pract. 2006;60:315-320.   DOI   ScienceOn
21 Bunkenburg B, Amelsvoort T, Rogg H, Wood JM. Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension. 1992;20:746-754.   DOI
22 Makita S, Nakamura M, Yoshida H, Hiramori K. Effect of angiotensin II receptor blocker on angiotensin II stimulated DNA synthesis of cultured human aortic smooth muscle cells. Life Sci. 1995;56:PL383-PL388.   DOI   ScienceOn
23 Herbert JM, Delisee C, Dol F, Schaeffer P, Cazaubon C, Nisato D, Chatelain P. Effect of SR 47436, a novel angiotensin II AT1 receptor antagonist, on human vascular smooth muscle cells in vitro. Eur J Pharmacol. 1994;251:143-150.   DOI   ScienceOn
24 Okada K, Hirano T, Ran J, Adachi M. Olmesartan medoxomil, an angiotensin II receptor blocker ameliorates insulin resistance and decreases triglyceride production in fructose-fed rats. Hypertens Res. 2004;27:293-299.   DOI   ScienceOn
25 Ross R. Cell biology of atherosclerosis. Annu Rev Physiol. 1995;57:791-804.   DOI   ScienceOn
26 Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. $Ca^{2+}$/calmodulin-dependent protein kinase kinase-beta acts upstream of AMPactivated protein kinase in mammalian cells. Cell Metab. 2005;2:21-33.   DOI   ScienceOn
27 Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003;546:113-120.   DOI   ScienceOn
28 Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271:27879-27887.   DOI   ScienceOn
29 Hardie DG. New roles for the LKB1-->AMPK pathway. Curr Opin Cell Biol. 2005;17:167-173.   DOI   ScienceOn
30 Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273:E1107-E1112.
31 Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem. 2002;277:23977-23980.   DOI   ScienceOn
32 Lee WJ, Lee IK, Kim HS, Kim YM, Koh EH, Won JC, Han SM, Kim MS, Jo I, Oh GT, Park IS, Youn JH, Park SW, Lee KU, Park JY. Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol. 2005;25:2488-2494.   DOI   ScienceOn