Journal
JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS
Volume 25, Issue 1, Pages 65-80Publisher
JAPAN ATHEROSCLEROSIS SOC
DOI: 10.5551/jat.37747
Keywords
Pitavastatin; Pleiotropic effect; Atherogenesis; Ischemia; eNOS
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Funding
- JSPS KAKENHI [25461389]
- Grant for a Study Group on Aseptic Femoral Neck Necrosis from the Ministry of Health, Labour and Welfare of Japan
- Grants-in-Aid for Scientific Research [25461389] Funding Source: KAKEN
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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.
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