Pitavastatin and Vascular Stress
Mitsuhashi, Takeshi Tokushima University
Uemoto, Ryoko Tokushima University
Ishikawa, Kazue Tokushima University
Ikeda, Yasumasa Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Matsumoto, Toshio Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Akaike, Masashi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Aim: Statins have a protective impact against cardiovascular diseases through not only lipid-lowering effects but also pleiotropic effects, including activation of the endothelial nitric oxide synthase (eNOS) system. We aimed to clarify the protective effects of a statin against atherogenesis and ischemia in eNOS－/－ mice.
Methods: Study 1. eNOS－/－ Apolipoprotein E (ApoE)－/－ mice were treated with a vehicle or pitavastatin (0.3 mg/kg/day) for 4 weeks. Study 2. eNOS－/－ mice were also treated with a vehicle or the same dose of pitavastatin for 2 weeks prior to hind-limb ischemia.
Results: In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS－/－ ApoE－/－ mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin-treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin-treated eNOS－/－ mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models.
Conclusion: Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.
Journal of Atherosclerosis and Thrombosis
Japan Atherosclerosis Society
Copyright©2018 Japan Atherosclerosis Society
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Institute of Advanced Medical Sciences