Mechanoregulation of Monocyte Chemoattractant Protein-1 Expression in Rat Vascular Smooth Muscle Cells

Abstract

The authors have previously shown that arterial wall strain mediates the development of vessel wall inflammation in experimental hypertension. The current studies explore the mechanoregulation of monocyte chemoattractant protein-1 (MCP-1), a potent pro-inflammatory chemokine, by mitogen-activated protein kinases(MAPK) and oxidative stress. Rat aortic smooth muscle (RASM) cells were subjected to cyclic strain on a uniform biaxial strain device. Strain rapidly activated both ERK1/2^MAPK and p38^MAPK, with peak activation at 5 min. Strain induced a twofold increase in MCP-1 mRNA, which was attenuated by PD 98059, a specific ERK1/2^MAPK inhibitor, and SB 203580, a specific p38^MAPK inhibitor. Cyclic strain also increased production of superoxide anion via an NADPH oxidase-dependent mechanism. To assess the potential role of reactive oxygen species in MAPK activation, cells were stretched in the presence of N-acetylcysteine, which had no effect on p38_MAPK activation, but significantly inhibited ERK1/2^MAPK activation and MCP-1 expression. In conclusion, redox-sensitive activation of ERK1/2^MAPK and redox-insensitive activation of p38^MAPK regulate straininduced MCP-1 expression in RASM cells. These findings define a role for MAPK signal transduction in establishing a pro-inflammatory state in the arterial wall, and thus implicate a potential molecular link between arterial wall strain and atherosclerosis.