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(Circulation Research. 2007;101:1104.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Systemic Deficiency of the MAP Kinase–Activated Protein Kinase 2 Reduces Atherosclerosis in Hypercholesterolemic Mice

Kumaravelu Jagavelu, Uwe J.F. Tietge, Matthias Gaestel, Helmut Drexler, Bernhard Schieffer^*, Udo Bavendiek^*

From the Department of Cardiology & Angiology (K.J., H.D., B.S., U.B.), Hannover Medical School, Germany; the Center for Liver, Digestive & Metabolic Diseases, Department of Pediatrics (U.J.F.T.), University Medical Center, Groningen, The Netherlands; and the Department of Biochemistry (M.G.), Hannover Medical School, Germany.

Correspondence to Udo Bavendiek, MD, Department of Cardiology & Angiology, Hannover Medical School, Carl-Neuberg-Str. 01, 30625 Hannover, Germany. E-mail Bavendiek.Udo{at}mh-hannover.de

Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. A critical regulator of inflammatory processes represents the mitogen-activated protein kinase–activated protein kinase-2 (MK2). Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice as well as potentially underlying mechanisms in vivo and in vitro. Activation of MK2 (phospho-MK2) was predominantly detected in the endothelium and macrophage-rich plaque areas within aortas of hypercholesterolemic LDL receptor–deficient mice (ldlr^–/–). Systemic MK2 deficiency of hypercholesterolemic ldlr^–/– mice (ldlr^–/–/mk2^–/–) significantly decreased the accumulation of lipids and macrophages in the aorta after feeding an atherogenic diet for 8 and 16 weeks despite a significant increase in proatherogenic plasma lipoproteins compared with ldlr^–/– mice. Deficiency of MK2 significantly decreased oxLDL-induced foam cell formation in vitro, diet-induced foam cell formation in vivo, and expression of scavenger receptor A in primary macrophages. In addition, systemic MK2 deficiency of hypercholesterolemic ldlr^–/– mice significantly decreased the aortic expression of the adhesion molecule VCAM-1 and the chemokine MCP-1, key mediators of macrophage recruitment into the vessel wall. Furthermore, silencing of MK2 in endothelial cells by siRNA reduced the IL-1ß–induced expression of VCAM-1 and MCP-1. MK2 critically promotes atherogenesis by fostering foam cell formation and recruitment of monocytes/macrophages into the vessel wall. Therefore, MK2 might represent an attractive novel target for the treatment of atherosclerotic cardiovascular disease.

Key Words: atherosclerosis • MK2 • hypercholesterolemic mice

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