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ID 115483
Title Alternative
Pitavastatin and Vascular Stress
Author
Mitsuhashi, Takeshi Tokushima University
Uemoto, Ryoko Tokushima University
Ishikawa, Kazue Tokushima University
Keywords
Pitavastatin
Pleiotropic effect
Atherogenesis
Ischemia
eNOS
Content Type
Journal Article
Description
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 Title
Journal of Atherosclerosis and Thrombosis
ISSN
18803873
13403478
Publisher
Japan Atherosclerosis Society
Volume
25
Issue
1
Start Page
65
End Page
80
Published Date
2018-01-01
Rights
Copyright©2018 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.(https://creativecommons.org/licenses/by-nc-sa/4.0/)
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language
eng
TextVersion
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departments
Medical Sciences
Institute of Advanced Medical Sciences