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Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells

2014; Japanese Circulation Society; Volume: 78; Issue: 9 Linguagem: Inglês

10.1253/circj.cj-14-0095

1347-4820

Tatsuya Noguchi, Yoshihiko Kakinuma, Mikihiko Arikawa, Kayo Okazaki, Eri Hoshino, Tatsuo Iiyama, Toru Kubo, Hiroaki Kitaoka, Yoshinori Doi, Takayuki Sato,

Stroke Rehabilitation and Recovery

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)