title: Inhibition of MCP-1/CCR2 signaling pathway is involved in synergistic inhibitory effects of irbesartan with rosuvastatin on vascular remodeling.
abstract: Additional beneficial effects of angiotensin II type 1 (AT(1)) receptor blockers beyond AT(1) receptor blockade have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2). We examined the possible synergistic effects of the combination of irbesartan with rosuvastatin on preventing vascular remodeling focusing on the MCP-1/CCR2 pathway. We observed that administration of irbesartan and CCR2 antagonist, propagermanium, at noneffective doses, decreased the neointima with a decrease in PCNA labeling index in the injured mouse femoral artery induced by cuff placement. We also observed that administration of a noneffective dose of rosuvastatin with propagermanium decreased the neointima area, suggesting that the inhibitory effect of rosuvastatin on neointima formation is at least partly attributable to blockade of the MCP-1/CCR2 pathway. Moreover, we demonstrated that the combination of irbesartan with rosuvastatin decreased neointima formation. MCP-1 mRNA level was significantly increased in injured femoral arteries, and administration of irbesartan with rosuvastatin decreased the mRNA levels of MCP-1, TNFα, and IL-1β, and increased PPARγ mRNA expression. These results suggest that the synergistic inhibitory effects of irbesartan with rosuvastatin on neointima formation may involve attenuation of MCP-1/CCR2 signaling.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Ehime, Japan.
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakaoka
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ogimoto
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000187:drug effects*; D004357:Drug Synergism; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D005464:Fluorobenzenes / Q000494:pharmacology*; D005857:Germanium; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000077405:Irbesartan; D051379:Mice; D058426:Neointima / Q000473:pathology / Q000517:prevention & control; D009942:Organometallic Compounds / Q000494:pharmacology; D011422:Propionates; D011743:Pyrimidines / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000187:drug effects*; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009942:Organometallic Compounds; D011422:Propionates; D011743:Pyrimidines; D054390:Receptors, CCR2; D013449:Sulfonamides; D013777:Tetrazoles; D005857:Germanium; C066750:propagermanium; D000068718:Rosuvastatin Calcium; D000077405:Irbesartan