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.