Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model
Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model
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DOI：
10.1016/j.yjmcc.2009.11.010
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发表时间：
2010-04-01
影响因子：
5
通讯作者：
Sato, Takayuki
中科院分区：
文献类型：
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作者：
Kakinuma, Yoshihiko;Furihata, Mutsuo;Sato, Takayuki
我们最近的研究表明，乙酰胆碱 (ACh) 通过激活 PI3K/Akt/HIF-1 α/VEGF 通路来保护心肌细胞免受长期缺氧的影响，并且心肌细胞衍生的 VEGF 以旁分泌方式促进血管生成。这些结果表明胆碱能系统在调节血管生成中发挥作用。因此，我们评估了这样的假设：胆碱能调节剂多奈哌齐（一种用于阿尔茨海默病的乙酰胆碱酯酶抑制剂）表现出有益的作用，特别是在加速血管生成方面。我们使用α7烟碱受体缺失小鼠（α7KO）和野生型小鼠（WT）的缺血后肢模型评估了多奈哌齐对体外和体内血管生成特性的影响。多奈哌齐激活血管生成信号，即 HIF-1 α 和 VEGF 表达，并加速人脐静脉内皮细胞 (HUVEC) 中的管形成。乙酰胆碱和尼古丁上调信号转导，加速管形成，表明多奈哌齐促进共同的血管生成途径。此外，多奈哌齐处理的WT表现出丰富的毛细血管，增强了VEGF和PCNA内皮表达，从受损的组织灌注中恢复，通过持续的肢体表面皮肤温度预防缺血诱导的肌肉萎缩，以及独立于α7受体抑制细胞凋亡。多奈哌齐在血管生成、组织灌注、生化标志物和表面皮肤温度方面对 α7 KO 发挥了相对更多的作用。多奈哌齐同时升高 WT 和 α 7 KO 心内内皮细胞中的 VEGF 表达，并进一步增加胆碱乙酰转移酶 (ChAT) 蛋白表达，这对于内皮细胞中 ACh 合成至关重要。本研究的结论是，多奈哌齐可以作为加速心血管疾病患者血管生成的治疗工具。 (c) 2009 Elsevier Ltd. 保留所有权利。
Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1 alpha/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits beneficial effects, especially on the acceleration of angiogenesis. We evaluated the effects of donepezil on angiogenic properties in vitro and in vivo, using an ischemic hindlimb model of alpha 7 nicotinic receptor-deleted mice (alpha 7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1 alpha and VEGF expression, and accelerated tube formation in human umbilical vein endothelial cells (HUVECs). ACh and nicotine upregulated signal transduction with acceleration of tube formation, suggesting that donepezil promotes a common angiogenesis pathway. Moreover, donepezil-treated WT exhibited rich capillaries with enhanced VEGF and PCNA endothelial expression, recovery from impaired tissue perfusion, prevention of ischemia-induced muscular atrophy with sustained surface skin temperature in the limb, and inhibition of apoptosis independent of the alpha 7 receptor. Donepezil exerted comparably more effects in alpha 7 KO in terms of angiogenesis, tissue perfusion, biochemical markers, and surface skin temperature. Donepezil concomitantly elevated VEGF expression in intracardiac endothelial cells of WT and alpha 7 KO and further increased choline acetyltransferase (ChAT) protein expression, which is critical for ACh synthesis in endothelial cells. The present study concludes that donepezil can act as a therapeutic tool to accelerate angiogenesis in cardiovascular disease patients. (c) 2009 Elsevier Ltd. All rights reserved.