Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model
| Autor: | Takemi Handa, Rajesh Katare, Yoshihiko Kakinuma, Takayuki Sato, Mutsuo Furihata, Mikihiko Arikawa, Tsuyoshi Akiyama |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Indocyanine Green
Vascular Endothelial Growth Factor A medicine.medical_specialty medicine.drug_class Angiogenesis Angiogenesis Pathway Biology Neovascularization Mice chemistry.chemical_compound Piperidines Alzheimer Disease Ischemia Internal medicine mental disorders medicine Animals Humans Donepezil Hypoxia Molecular Biology Caspase 7 Mice Knockout Tube formation Neovascularization Pathologic Caspase 3 Endothelial Cells Acetylcholine Hindlimb Vascular endothelial growth factor Endocrinology Microscopy Fluorescence Acetylcholinesterase inhibitor chemistry Indans Cholinergic Cholinesterase Inhibitors medicine.symptom Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | Journal of molecular and cellular cardiology. 48(4):680-693 |
| ISSN: | 0022-2828 |
| Popis: | Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1alpha/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 alpha7 nicotinic receptor-deleted mice (alpha7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1alpha 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 alpha7 receptor. Donepezil exerted comparably more effects in alpha7 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 alpha7 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. |
| Databáze: | OpenAIRE |
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