Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice

Po Hsun Huang, Jian You Chen, Chi Yu Chen, Jaw Wen Chen, Shing Jong Lin, Chun Che Shih

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objective In contrast to statins, ezetimibe belongs to a new class of cholesterol-lowering agent not known to mediate pleiotropic effects. Here we investigate whether ezetimibe or simvastatin can help recover blood flow and reduce tissue damage after hindlimb ischemia surgery in diabetic mice. Methods Diabetic mice were created by intraperitoneal streptozotocin injection in male FVB/NJ mice. All diabetic mice were subsequently divided into three groups: diabetic control, diabetic with simvastatin (0.2 mg/kg), and diabetic with ezetimibe (0.1 mg/kg). All experimental mice received hindlimb ischemia surgery after 2 weeks of drug treatment. Circulating endothelial progenitor cell number was determined by flow cytometry (Sca-1+/C-kit+/Flk-1+) in peripheral blood. Results In comparison to the mice in the diabetic control group (n = 6), wild-type mice (n = 6) and diabetic mice that received simvastatin (n = 6) had significantly increased ischemic/nonischemic limb blood perfusion ratio, higher capillary density (P <.05, respectively), and reduced ischemic limb damage (diabetic control, 80%; diabetic with simvastatin, 40%; diabetic with ezetimibe, 80%). However, these proangiogenic effects were not observed in diabetic mice that had been treated with ezetimibe. In addition, the number of ischemia-triggered endothelial progenitor cells in peripheral blood was significantly enhanced in the wild-type mice and in the diabetic mice being treated with simvastatin, but not in those being treated with ezetimibe, after ischemic surgery. Endothelial nitric oxide synthase activity as determined by acetylcholine-stimulated vasorelaxation recovered notably in diabetic mice that were treated with simvastatin but was not improved by ezetimibe (n = 6, each group). Moreover, simvastatin led to a significant upregulation of endothelial nitric oxide synthase phosphorylation; vascular endothelial growth factor protein levels in ischemic tissues were also increased. By contrast, administration of ezetimibe did not produce these effects. Conclusions Simvastatin helped recover blood flow and reduce tissue damage in ischemic hindlimbs and also promoted new vessel formation in streptozotocin-treated mice, whereas ezetimibe did not. These results may help explain why statins and ezetimibe decrease cholesterol levels, whereas their pleiotropic effects on vasoprotective functions independent of low-density lipoprotein cholesterol lowering are different.

Original languageEnglish
Pages (from-to)1112-1120.e1
JournalJournal of Vascular Surgery
Volume64
Issue number4
DOIs
Publication statusPublished - Oct 1 2016
Externally publishedYes

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Simvastatin
Streptozocin
Ischemia
Hindlimb
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Nitric Oxide Synthase Type III
Extremities
Cholesterol
Ezetimibe
Control Groups
Intraperitoneal Injections
Vasodilation
LDL Cholesterol
Vascular Endothelial Growth Factor A
Acetylcholine
Flow Cytometry
Up-Regulation

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice. / Huang, Po Hsun; Chen, Jian You; Chen, Chi Yu; Chen, Jaw Wen; Lin, Shing Jong; Shih, Chun Che.

In: Journal of Vascular Surgery, Vol. 64, No. 4, 01.10.2016, p. 1112-1120.e1.

Research output: Contribution to journalArticle

Huang, Po Hsun ; Chen, Jian You ; Chen, Chi Yu ; Chen, Jaw Wen ; Lin, Shing Jong ; Shih, Chun Che. / Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice. In: Journal of Vascular Surgery. 2016 ; Vol. 64, No. 4. pp. 1112-1120.e1.
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AU - Shih, Chun Che

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N2 - Objective In contrast to statins, ezetimibe belongs to a new class of cholesterol-lowering agent not known to mediate pleiotropic effects. Here we investigate whether ezetimibe or simvastatin can help recover blood flow and reduce tissue damage after hindlimb ischemia surgery in diabetic mice. Methods Diabetic mice were created by intraperitoneal streptozotocin injection in male FVB/NJ mice. All diabetic mice were subsequently divided into three groups: diabetic control, diabetic with simvastatin (0.2 mg/kg), and diabetic with ezetimibe (0.1 mg/kg). All experimental mice received hindlimb ischemia surgery after 2 weeks of drug treatment. Circulating endothelial progenitor cell number was determined by flow cytometry (Sca-1+/C-kit+/Flk-1+) in peripheral blood. Results In comparison to the mice in the diabetic control group (n = 6), wild-type mice (n = 6) and diabetic mice that received simvastatin (n = 6) had significantly increased ischemic/nonischemic limb blood perfusion ratio, higher capillary density (P <.05, respectively), and reduced ischemic limb damage (diabetic control, 80%; diabetic with simvastatin, 40%; diabetic with ezetimibe, 80%). However, these proangiogenic effects were not observed in diabetic mice that had been treated with ezetimibe. In addition, the number of ischemia-triggered endothelial progenitor cells in peripheral blood was significantly enhanced in the wild-type mice and in the diabetic mice being treated with simvastatin, but not in those being treated with ezetimibe, after ischemic surgery. Endothelial nitric oxide synthase activity as determined by acetylcholine-stimulated vasorelaxation recovered notably in diabetic mice that were treated with simvastatin but was not improved by ezetimibe (n = 6, each group). Moreover, simvastatin led to a significant upregulation of endothelial nitric oxide synthase phosphorylation; vascular endothelial growth factor protein levels in ischemic tissues were also increased. By contrast, administration of ezetimibe did not produce these effects. Conclusions Simvastatin helped recover blood flow and reduce tissue damage in ischemic hindlimbs and also promoted new vessel formation in streptozotocin-treated mice, whereas ezetimibe did not. These results may help explain why statins and ezetimibe decrease cholesterol levels, whereas their pleiotropic effects on vasoprotective functions independent of low-density lipoprotein cholesterol lowering are different.

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