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Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice  Po-Hsun Huang, MD, PhD,

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Presentation on theme: "Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice  Po-Hsun Huang, MD, PhD,"— Presentation transcript:

1 Simvastatin pretreatment enhances ischemia-induced neovascularization and blood flow recovery in streptozotocin-treated mice  Po-Hsun Huang, MD, PhD, Jian-You Chen, MS, Chi-Yu Chen, MS, Jaw-Wen Chen, MD, Shing-Jong Lin, MD, PhD, Chun-Che Shih, MD, PhD  Journal of Vascular Surgery  Volume 64, Issue 4, Pages e1 (October 2016) DOI: /j.jvs Copyright © 2016 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Effects of simvastatin and ezetimibe on blood flow recovery after hindlimb ischemia in wild-type (WT) mice and streptozotocin (STZ)-treated mice. A, Representative results of laser Doppler measurements obtained before and 4 weeks after hindlimb ischemia surgery in WT control mice (vehicle), diabetic (DM) control mice, and diabetic mice treated with simvastatin and ezetimibe (DM+Sim, DM+Eze; n = 6 for each group). B, Color scale illustrates blood flow variations from minimal (dark blue) to maximal (red) values. The arrows indicate ischemic (right) limb after hindlimb ischemia surgery. Doppler perfusion ratios (ischemic/nonischemic hindlimb) over time in the different groups. Results are mean ± standard error of mean. ∗P < .05 compared with WT mice; #P < .05 compared with DM-control mice (n = 6 for each group). Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Effects of simvastatin and ezetimibe on spontaneous foot amputation and new vessel formation after hindlimb ischemia in wild-type (WT) mice and streptozotocin (STZ)-treated mice. A, After hindlimb ischemia surgery, diabetic (DM) control mice and diabetic mice treated with ezetimibe (DM+Eze; 80%) suffered from spontaneous foot amputation, but only 20% of WT mice and 40% of diabetic mice treated with simvastatin (DM+Sim) had ischemia-induced foot amputation (n = 6 for each group). B, Histologic analysis revealed that the capillary density in the ischemic limb was significantly decreased in DM mice compared with WT mice and DM+Sim mice, whereas no such increase was observed in DM+Eze mice (n = 6 for each group). P < .05 compared with DM-control mice. Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Effects of simvastatin and ezetimibe on endothelial progenitor cell (EPC) mobilization in wild-type (WT) mice and streptozotocin (STZ)-treated mice. A, Mobilization of EPCs (defined as Sca-1+/C-kit+/Flk-1+ cells) after tissue ischemia was determined by flow cytometry in WT mice and in STZ-induced diabetic (DM) mice that were administered the vehicle, simvastatin (DM+Sim), or ezetimibe (DM+Eze; n = 6 for each group). B, Plasma levels of stromal cell-derived factor 1 (SDF-1) were also determined in peripheral blood in mice before and 1 week after hindlimb ischemia surgery (n = 6 in each group). Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Restoration of endothelial dysfunction by simvastatin in streptozotocin (STZ)-treated mice. Thoracic aorta were excised from wild-type (WT) mice and diabetic (DM) mice treated with either simvastatin or ezetimibe (n = 4 for each group). Relaxation of thoracic aorta in response to acetylcholine (Ach) was measured. P < .05 compared with DM-control mice. Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

6 Fig 5 A, Simvastatin resulted in upregulation of endothelial nitric oxide synthase (eNOS) phosphorylation and vascular endothelial growth factor (VEGF) in ischemic muscle. B and C, Simvastatin enhanced expressions of phosphorylated eNOS (p-eNOS) at Ser1177 and VEGF in ischemic muscle. After treatment with simvastatin, streptozotocin (STZ)-induced diabetic (DM) mice had significantly increased expressions of phosphorylation of eNOS and VEGF in ischemic tissues compared with DM-control mice. Administration of ezetimibe did not enhance phosphorylation of eNOS and VEGF expression in ischemic muscle (two samples per animal, three mice in each group). #P < .05 compared with wild type (WT); ∗P < .05 compared with DM-control. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

7 Supplementary Fig (online only)
Effects of simvastatin and ezetimibe on blood flow recovery after hindlimb ischemia in wild-type (WT) and low-density lipoprotein receptor knockout (LDLR KO) mice. A, Doppler perfusion ratio (ischemic/nonischemic hindlimb) measurements obtained before and 4 weeks after hindlimb ischemia surgery in WT mice. B, Doppler perfusion ratio (ischemic/nonischemic hindlimb) measurements obtained before and 4 weeks after hindlimb ischemia surgery in LDLR KO mice. Results are mean ± standard deviation. ∗P < .05 compared with LDLR KO mice—control group. Journal of Vascular Surgery  , e1DOI: ( /j.jvs ) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

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