Angiotensin II Induces Monocyte Chemoattractant Protein-1 Gene Expression in Rat Vascular Smooth Muscle Cells

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine (X.C., P.E.T., M.T.O., R.W.A., R.M.M.), Atlanta, Ga, and AtheroGenics, Inc (R.M.M.), Norcross, Ga.

Correspondence to Russell M. Medford, MD, PhD, AtheroGenics, Inc, 3065 Northwoods Circle, Norcross, GA 30071. E-mail rmedford{at}atherogen.com

Abstract—Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT₁ receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H₂O₂, with diphenylene iodonium or apocynin decreased Ang II–induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H₂O₂. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II–induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.

Key Words: angiotensin II • monocyte chemoattractant protein-1 • vascular smooth muscle cell • AT₁ receptor

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				G. W. De Keulenaer, M. Ushio-Fukai, Q. Yin, A. B. Chung, P. R. Lyons, N. Ishizaka, K. Rengarajan, W. R. Taylor, R. W. Alexander, and K. K. Griendling Convergence of Redox-Sensitive and Mitogen-Activated Protein Kinase Signaling Pathways in Tumor Necrosis Factor-{alpha}-Mediated Monocyte Chemoattractant Protein-1 Induction in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 385 - 391. [Abstract] [Full Text] [PDF]

				C. Kunsch and R. M. Medford Oxidative Stress as a Regulator of Gene Expression in the Vasculature Circ. Res., October 15, 1999; 85(8): 753 - 766. [Abstract] [Full Text] [PDF]

				Y.-M. Go, R. P. Patel, M. C. Maland, H. Park, J. S. Beckman, V. M. Darley-Usmar, and H. Jo Evidence for peroxynitrite as a signaling molecule in flow-dependent activation of c-Jun NH2-terminal kinase Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1647 - H1653. [Abstract] [Full Text] [PDF]

				T. Kita LOX-1, a Possible Clue to the Missing Link Between Hypertension and Atherogenesis Circ. Res., May 14, 1999; 84(9): 1113 - 1115. [Full Text] [PDF]

				H. P. Brunner-La Rocca, G. Vaddadi, and M. D. Esler Recent insight into therapy of congestive heart failure: focus on ACE inhibition and angiotensin-II antagonism J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1163 - 1173. [Abstract] [Full Text] [PDF]