title: Synergistic Inhibitory Effect of Rosuvastatin and Angiotensin II Type 2 Receptor Agonist on Vascular Remodeling.
abstract: We investigated the possibility that coadministration of rosuvastatin and compound 21 (C21), a selective angiotensin II type 2 (AT2) receptor agonist, could exert synergistic preventive effects on vascular injury. Vascular injury was induced by polyethylene cuff placement on the femoral artery in 9-week-old male C57BL/6J mice. Mice were treated with rosuvastatin and/or with C21 after cuff placement. Neointima formation was determined 14 days after the operation and cell proliferation, and superoxide anion production and expression of inflammatory cytokines were examined 7 days after cuff placement. Neointima formation was significantly attenuated by the treatment of rosuvastatin (5 mg kg(-1) day(-1)) or C21 (10 μg kg(-1) day(-1)), associated with the decreases in proliferating cell nuclear antigen (PCNA) labeling index, oxidative stress, and the expression of inflammatory markers. Treatment with a noneffective dose of rosuvastatin (0.5 mg kg(-1) day(-1)) plus a low dose of C21 (1 μg kg(-1) day(-1)) inhibited the PCNA labeling index, superoxide anion production, mRNA expressions of NAD(P)H subunits, and mRNA and protein expressions of inflammatory markers associated with marked inhibition of neointima formation. Angiotensin II type 1 (AT1) receptor mRNA expression did not differ the groups. By contrast, AT2 receptor mRNA expression was increased by administration of C21 at the dose of 10 μg kg(-1) day(-1) but not by C21 at the dose of 1 μg kg(-1) day(-1) or rosuvastatin. The combination of rosuvastatin and AT2 receptor agonist exerted synergistic preventive effects on vascular remodeling associated with the decreases in cell proliferation, oxidative stress, and inflammatory reaction. That could be a powerful approach to vascular disease prevention.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Bai
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan mmogi@m.ehime-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kan-No
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Bao-Shuai
authors.initials: BS
authors.lastname: Shan
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kukida
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Higaki
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology (H.-Y.B., M.M., H.N., H.K., K.T., X.-L.W., B.-S.S., M.K., T.Y., A.H., L.M., J.I., M.H.), Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.K., A.H.), and Department of Pediatrics (T.Y.), Graduate School of Medicine, Ehime University, Shitsukawa, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D051379:Mice; D058426:Neointima / Q000188:drug therapy; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000235:genetics; D000068718:Rosuvastatin Calcium / Q000494:pharmacology* / Q000627:therapeutic use; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III