title: Angiotensin II and tumor necrosis factor-alpha synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-kappaB, p38, and reactive oxygen species.
abstract: We examined whether ANG II and TNF-alpha cooperatively induce vascular inflammation using the expression of monocyte chemoattractant protein (MCP)-1 as a marker of vascular inflammation. ANG II and TNF-alpha stimulated MCP-1 expression in a synergistic manner in vascular smooth muscle cells. ANG II-induced MCP-1 expression was potently inhibited to a nonstimulated basal level by blockade of the p38-dependent pathway but only partially inhibited by blockade of the NF-kappaB-dependent pathway. In contrast, TNF-alpha-induced MCP-1 expression was potently suppressed by blockade of NF-kappaB activation but only modestly suppressed by blockade of p38 activation. ANG II- and TNF-alpha-induced activation of NF-kappaB- and p38-dependent pathways was partially inhibited by pharmacological inhibitors of ROS production. Furthermore, ANG II- and TNF-alpha-stimulated MCP-1 expression was partially suppressed by ROS inhibitors. We also examined whether endogenous ANG II and TNF-alpha cooperatively promote vascular inflammation in vivo using a wire injury model of the rat femoral artery. Blockade of both ANG II and TNF-alpha further suppressed neointimal formation, macrophage infiltration, and MCP-1 expression in an additive manner compared with blockade of ANG II or TNF-alpha alone. These results suggested that ANG II and TNF-alpha synergistically stimulate MCP-1 expression via the utilization of distinct intracellular signaling pathways (p38- and NFkappaB-dependent pathways) and that these pathways are activated in ROS-dependent and -independent manners. These results also suggest that ANG II and TNF-alpha cooperatively stimulate vascular inflammation in vivo as well as in vitro.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Takahashi
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Takeda
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Oba
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D018014:Gene Transfer Techniques; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism; D015854:Up-Regulation; D014657:Vasculitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; D048051:p38 Mitogen-Activated Protein Kinases