Chylomicron remnants induce monocyte chemoattractant protein-1 expression via p38 MAPK activation in vascular smooth...

Chylomicron remnants, major lipoproteins at postprandial hyperlipidemia, have been considered to be proatherogenic lipoproteins. However, the mechanisms by which chylomicron remnants enhance atherosclerosis have not been fully understood. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine which stimulates migration of monocytes and plays a critical role in the development of atherosclerosis. In this study, we investigated the effect of chylomicron remnants on MCP-1 expression in cultured vascular smooth muscle cells (VSMCs). We prepared chylomicrons from the lymph of gastrostomized rats fed with egg solution and obtained chylomicron remnants from the plasma of hepatectomized rats which were injected with chylomicrons. Treatment of VSMC with chylomicron remnants resulted in a significant increase of the expression of MCP-1 mRNA and protein in a time-and a dose-dependent manner. Further, chylomicron remnants activated p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2). Pretreatment of VSMCs with p38 MAPK inhibitors, SB203580 and SB202190, resulted in a dose-dependent inhibition of chylomicron remnants-induced MCP-1 mRNA and protein expression, whereas a MAPK kinase inhibitor, PD98059, had no effect on these responses. MCP-1 secretion by chylomicron remnants was much more pronounced than those by chylomicrons, oxidized low-density lipoproteins, or lysophosphatidylcholine. These results indicated that chylomicron remnants stimulated MCP-1 expression in VSMCs, and suggested that chylomicron remnants might contribute to the formation of atherosclerosis through this proinflammatory effect.