Mechanoregulation of monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells.
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.
Guest
Thomas M
TM
Division of Cardiology, Atlanta VAMC and Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Vlastos
George
G
Alameddine
Fadi M F
FM
Taylor
W Robert
WR
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D000074624:NADPH Oxidase 1; D010084:Oxidation-Reduction; D010766:Phosphorylation; D010812:Physical Stimulation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D016372:RNA, Antisense / Q000235:genetics; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005419:Flavonoids; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016372:RNA, Antisense; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine