Systemic deficiency of the MAP kinase-activated protein kinase 2 reduces atherosclerosis in hypercholesterolemic mice.
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-1beta-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.
Jagavelu
Kumaravelu
K
Department of Cardiology & Angiology, Hannover Medical School, Carl-Neuberg-Str. 01, 30625 Hannover, Germany.
Tietge
Uwe J F
UJ
Gaestel
Matthias
M
Drexler
Helmut
H
Schieffer
Bernhard
B
Bavendiek
Udo
U
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000032:analysis; D004730:Endothelium, Vascular / Q000201:enzymology; D005487:Foam Cells / Q000473:pathology; D006937:Hypercholesterolemia / Q000150:complications*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D051116:Receptors, Scavenger / Q000032:analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis; D000099190:MAP-Kinase-Activated Kinase 2
D018932:Chemokine CCL2; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; D017346:Protein Serine-Threonine Kinases; D051116:Receptors, Scavenger; D019010:Vascular Cell Adhesion Molecule-1; D000099190:MAP-Kinase-Activated Kinase 2