Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice
Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice
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DOI：
10.1016/j.biopha.2007.06.014
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发表时间：
2008-01-01
影响因子：
7.5
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Huang, Po-Hsun;Sata, Masataka;Nagai, Ryozo
血管生成，即新血管的形成，是对组织缺血的生理反应。临床证据表明，糖尿病患者因缺血而出现内皮功能障碍和血管生成受损。在这里，我们研究了糖尿病对缺血诱导的侧支生长的影响，并测试了过氧化物酶体增殖物激活受体-γ（PPAR γ）激动剂增加缺血组织侧支血流的假设。我们在KKAy小鼠中进行了单侧后肢缺血手术。通过激光多普勒成像测定，与野生型小鼠相比，糖尿病小鼠的血流恢复明显受损。用吡格列酮治疗KKAy小鼠部分恢复了血流恢复。抗CD 31免疫组化显示，吡格列酮也显着改善缺血肢体肌肉毛细血管密度。通过乙酰胆碱引起的血管舒张反应测定，吡格列酮治疗的糖尿病小鼠的内皮型一氧化氮合酶（eNOS）活性得到改善。吡格列酮使KKAy小鼠缺血肌肉中血管内皮生长因子（VEGF）蛋白水平正常化，并上调缺血肌肉中eNOS Ser-1177磷酸化和Akt Ser-473磷酸化。吡格列酮对N-G-硝基-L-精氨酸治疗的糖尿病小鼠的血流恢复没有有益作用。甲酯（L-NAME）。我们的研究结果表明，吡格列酮显着改善内皮功能障碍，并提高组织缺血后糖尿病小鼠的血流恢复。eNOS的激活似乎是必不可少的吡格列酮，以促进缺血组织中的血管生成。(c)2007年，Elsevier Masson SAS。All rights reserved.
Angiogenesis, the formation of new blood vessels, is a physiological response to tissue ischemia. Clinical evidence suggests that diabetic patients have endothelial dysfunction and impaired angiogenesis in response to ischemia. Here, we investigated the impact of diabetes on ischemia-induced collateral growth, and tested the hypothesis that peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist augments collateral flow to ischemic tissue. We conducted unilateral hindlimb ischemia surgery in KKAy mice. Blood flow recovery was markedly impaired in diabetic mice compared with that in wild-type mice as determined by laser Doppler imaging. Treatment of KKAy mice with pioglitazone partially restored the blood flow recovery. Anti-CD31 immunostaining revealed that pioglitazone also significantly improved the capillary density in ischemic limb muscle. Endothelial NO synthase (eNOS) activity was ameliorated in diabetic mice treated with pioglitazone as determined by vasorelaxation in response to acetylcholine. Pioglitazone normalized vascular endothelial growth factor (VEGF) protein levels, which was decreased in ischemic muscle of KKAy mice, and up-regulated eNOS phosphorylation at Ser-1177 and Akt phosphorylation at Ser-473 in ischemic muscle. Pioglitazone had no beneficial effects on blood flow recovery in diabetic mice treated with N-G-nitro-L-arginine. methyl ester (L-NAME). Our findings demonstrate that pioglitazone significantly ameliorates endothelial dysfunction and enhances blood flow recovery after tissue ischemia in diabetic mice. Activation of eNOS appears to be essential for pioglitazone to promote angiogenesis in ischemic tissue. (c) 2007 Elsevier Masson SAS. All rights reserved.