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Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice

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 is...

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Detalles Bibliográficos
Autores principales: Mitsuhashi, Takeshi, Uemoto, Ryoko, Ishikawa, Kazue, Yoshida, Sumiko, Ikeda, Yasumasa, Yagi, Shusuke, Matsumoto, Toshio, Akaike, Masashi, Aihara, Ken-ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Japan Atherosclerosis Society 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770225/
https://www.ncbi.nlm.nih.gov/pubmed/28592707
http://dx.doi.org/10.5551/jat.37747
Descripción
Sumario: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 hindlimb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.