Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells
Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells
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DOI：
10.1253/circj.cj-14-0095
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发表时间：
2014-09-01
影响因子：
3.3
通讯作者：
Sato, Takayuki
中科院分区：
文献类型：
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作者：
Noguchi, Tatsuya;Kakinuma, Yoshihiko;Sato, Takayuki
背景资料：通过加速患肢的血管生成来挽救更多外周动脉疾病（PAD）患者的肢体免于截肢已被期待多年。我们假设抗阿尔茨海默病药物多奈哌齐（DPZ）可以激活卫星细胞、肌源性祖细胞的血管肌生成特性，从而成为针对PAD的额外药理学疗法。在小鼠后肢缺血模型中，我们研究了临床剂量的DPZ的血管生成作用，（0.2mg kg（-1）day（-1））及其与西洛他唑（血小板聚集抑制剂和针对PAD的常规治疗药物）的组合。联合治疗最有效地改善了皮肤的寒冷和最有效地上调血管内皮生长因子（VEGF）产生的卫星细胞在缺血后肢。计算机断层扫描显示，DPZ显着衰减缺血性肌肉萎缩，并诱导受影响的后肢超恢复。人主动脉内皮细胞的体外研究表明，DPZ或其与西洛他唑的组合有效地上调pAkt、缺氧诱导因子-1 α和VEGF蛋白的表达。同样，在原代培养的卫星细胞，DPZ，单独或组合，上调VEGF，白细胞介素-1 β，和成纤维细胞生长因子2蛋白的表达。结论：目前的研究结果表明，临床剂量的DPZ加速血管平滑肌生成直接作用于内皮细胞和卫星细胞。因此，DPZ是传统药物治疗PAD的潜在额外选择。
Background: Saving more limbs of patients with peripheral arterial disease (PAD) from amputation by accelerating angiogenesis in affected limbs has been anticipated for years. We hypothesized that an anti-Alzheimer drug, donepezil (DPZ), can activate angiomyogenic properties of satellite cells, myogenic progenitors, and thus be an additional pharmacological therapy against PAD.Methods and Results: In a murine hindlimb ischemia model, we investigated the angiogenic effects of a clinical dose of DPZ (0.2mg kg(-1) day(-1)) and its combination with cilostazol, a platelet aggregation inhibitor and a conventional therapeutic drug against PAD. The combination therapy most effectively improved skin coldness and most effectively upregulated vascular endothelial growth factor (VEGF)-producing satellite cells in ischemic hindlimbs. Computed tomography revealed that DPZ remarkably attenuated ischemic muscle atrophy and induced super-restoration in affected hindlimbs. The in vitro study with human aortic endothelial cells showed that DPZ or its combination with cilostazol effectively upregulated the expression of pAkt, hypoxia inducible factor-1 alpha, and VEGF protein. Likewise, in primary cultured satellite cells, DPZ, alone or in combination, upregulated the expression of VEGF, interleukin-1 beta, and fibroblast growth factor 2 protein.Conclusions: The present results suggest that a clinical dosage of DPZ accelerates angiomyogenesis by directly acting on both endothelial and satellite cells. Therefore, DPZ is a potential additional choice for conventional drug therapy against PAD.