Abstract 307: Systemic Deficiency Of The Map Kinase Activated Protein Kinase 2 Reduces Atherosclerosis In Hypercholesterolemic Mice
Background: Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. The mitogen activated protein kinase (MAPK) activated protein kinase 2 (MAPKAP-2, MK2), a direct substrate of the stress activated MAPK p38α/β, critically regulates inflammatory processes such as production of inflammatory mediators (e. g. TNFα, IL-6) as recently demonstrated in vitro and in vivo. Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice in vivo as well as potentially underlying mechanisms in vitro.
Methods & Results: 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 ldlr−/− -mice (ldlr−/− /mk2−/−) significantly decreased accumulation of macrophages (MOMA-2 staining: −50%, n = 8–10, p < 0.001) and lipids (oil-red-O staining: −55%, n = 8–10, p< 0.001) in the aortic arch (cryo-sections) as well as lipid-depositions in the aorta descendens (en face, oil-red-O: −70%, n = 8–10, p < 0.001) after feeding an atherogenic diet for 8 or 16 weeks. MK2-deficiency significantly decreased oxLDL-induced foam cell formation in vitro (oil-red-O positive cells, dil-oxLDL-uptake: −50%, n = 3–5, p < 0.01), diet-induced foam cell formation in vivo (16 weeks atherogenic diet, oil-red-O positive cells: −60%, n = 3, p < 0.05) and expression of scavenger receptor A in peritoneal macrophages (qRT-PCR, westernblot: −70%, n = 3–5, p < 0.05). In addition, silencing of MK2-expression in endothelial cells by siRNA markedly and significantly reduced the IL-1β-induced expression of the adhesion molecule VCAM-1 (westernblot, n = 3) and the chemokine MCP-1 (ELISA: −40%, n = 5, p < 0.01). In line, MK2-deficiency significantly reduced VCAM-1 expression in the endothelium of ldlr−/− -mice in vivo (aortic arch, immunhistochemistry, −60%, n = 8, p < 0.01).
Conclusions: 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.