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.
- Received February 25, 2016.
- Accepted May 23, 2016.
This study was supported by JSPS KAKENHI [Grant 25293310 (to M.H.), 25462220 (to M.M.), 15K19974 (to J.I.), and 26860567 (to L.M.)], and research grants from the following pharmaceutical companies: Ajinomoto Pharmaceuticals Co. Ltd., Astellas Pharma Inc., Bayer Yakuhin Ltd., Daiichi-Sankyo Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Shionogi & Co. Ltd., and Takeda Pharmaceutical Co. Ltd.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics