RESUMEN
BACKGROUND: Endothelial progenitor cell (EPC) has significant age-dependent alterations in properties, but the role of Jagged1 in aging-induced decline of EPC functions remains unclear. METHODS: 2- and 20-month old healthy male Sprague-Dawley rats were used in present study. Jagged1 gene transfection was performed in EPC isolated from aged (AEPC) and young rats (YEPC), respectively. Experiments were divided into 4 groups: (1) pIRES2-EGFP (PE) group, (2) PE-combined N-[N-(3, 5-difluoro-phenacetyl)-1- alany1]-S-phenyglycine t-butyl ester (DAPT) (PE + D) group, (3) pIRES2 EGFP-Jagged1 (PEJ) group, and (4) PEJ combined DAPT (PEJ + D) group. Notch molecules were detected by real-time quantitative polymerase chain reaction or Western blotting. CD34, CD133, CD45, and KDR markers were detected by flow cytometry. EPC migration and proliferation were detected with a modified Boyden chamber and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, respectively; the tube formation ability was assayed by in vitro angiogenesis kit; EPC transfusion after Jagged1 gene transfection was performed in rat carotid artery injury models. RESULTS: Jagged1 gene transfection effectively activates notch-signaling pathway. Compared with PE groups, overexpression of Jagged1 significantly promoted AEPC functions including proliferation, migration, the tube formation ability, and cell differentiation, these effects could be reasonably diminished by DAPT. In vivo study demonstrated that Jagged1 overexpressing also significantly promoted AEPC homing to the vascular injury sites and decreases the neointima formation after vascular injury. CONCLUSIONS: Overexpression of Jagged1 ameliorates aged rat-derived EPC functions and increases its transfusion efficiency for balloon-induced rat arterial injury.
Asunto(s)
Angioplastia de Balón/efectos adversos , Traumatismos de las Arterias Carótidas/cirugía , Arteria Carótida Común/metabolismo , Células Progenitoras Endoteliales/trasplante , Proteína Jagged-1/metabolismo , Neovascularización Fisiológica , Factores de Edad , Animales , Apoptosis , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Arteria Carótida Común/patología , Movimiento Celular , Proliferación Celular , Células Cultivadas , Células Progenitoras Endoteliales/metabolismo , Proteína Jagged-1/genética , Masculino , Neointima , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Transfección , Regulación hacia ArribaRESUMEN
The dysfunction of endothelial progenitor cells (EPCs) was found to be associated with vascular complications in diabetes mellitus (DM) patients. Previous studies found that regular exercise could improve the function of EPCs in DM patients, but the underling mechanism was unclear. Irisin, a newly identified myokine, was induced by exercise and has been demonstrated to mediate some of the positive effects of exercise. In this study, we hypothesize that irisin may have direct effects on EPC function in DM mice. These data showed for the first time that irisin increased the number of EPCs in peripheral blood of DM mice and improved the function of EPCs derived from DM mice bone marrow. The mechanism for the effect of irisin is related to the PI3K/Akt/eNOS pathway. Furthermore, irisin was demonstrated to improve endothelial repair in DM mice that received EPC transplants after carotid artery injury. The results of this study indicate a novel effect of irisin in regulating the number and function of EPCs via the PI3K/Akt/eNOS pathway, suggesting a potential for the administration of exogenous irisin as a succedaneum to improve EPC function in diabetic patients who fail to achieve such improvements through regular exercise.