Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells
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概要
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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 (0.2 mg·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-1α, and VEGF protein. Likewise, in primary cultured satellite cells, DPZ, alone or in combination, upregulated the expression of VEGF, interleukin-1β, 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. (Circ J 2014; 78: 2317–2324)
- 一般社団法人 日本循環器学会の論文
著者
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Okazaki Kayo
Department Of Biology Tokyo Metropolitan University
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Noguchi Tatsuya
Department Of Applied Chemistry Muroran Institute Of Technology
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Kakinuma Yoshihiko
Department Of Cardiovascular Control Kochi Medical School
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Arikawa Mikihiko
Department Of Biological Science And Environment Graduate School Of Human Culture Nara Women's
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Sato Takayuki
Department Of Biomolecular Engineering Graduate School Of Bioscience And Biotechnology Tokyo Institu
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Kitaoka Hiroaki
Department Of Cardiology Kokura Memorial Hospital
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Iiyama Tatsuo
Clinical Research Center Kochi Medical School
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Doi Yoshinori
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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HOSHINO Eri
Clinical Trial Center, Kochi Medical School, Kochi University
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Kubo Toru
Department of Medical and Geriatrics, Kochi Medical School
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Doi Yoshinori
Department of Medical and Geriatrics, Kochi Medical School
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Hoshino Eri
Clinical Trial Center, Kochi Medical School
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Okazaki Kayo
Department of Cardiovascular Control, Kochi Medical School
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