Transcriptional regulation of Bim by FOXO3a and Akt mediates scleroderma serum-induced apoptosis in endothelial progenitor cells.
Transcriptional regulation of Bim by FOXO3a and Akt mediates scleroderma serum-induced apoptosis in endothelial progenitor cells.
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DOI：
10.1161/circulationaha.108.787200
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发表时间：
2008-11-18
期刊：
影响因子：
37.8
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Zhu S;Evans S;Yan B;Povsic TJ;Tapson V;Goldschmidt-Clermont PJ;Dong C
Endothelial progenitor cells (EPCs) contribute to vascular regeneration/repair, and may thus protect against scleroderma vasculopathy. We aimed to determine (i) whether circulating EPCs were reduced in scleroderma; and (ii) whether scleroderma sera could induce EPC apoptosis and, if so, what the underlying apoptotic signaling pathway was. Circulating EPC levels were quantified in 54 patients with scleroderma and 18 healthy controls by colony forming unit assay and flow cytometry, which revealed markedly decreased EPC levels in scleroderma patients relative to healthy subjects. Substantial apoptosis was detected in EPCs after culturing in the presence of scleroderma sera, compared to normal sera. Intriguingly, depletion of IgG fraction from SSc sera completely abolished the apoptotic effects. Furthermore, SSc sera inhibited the activation/phosphorylation of Akt, which in turn suppressed the phosphorylation and degradation of forkhead transcription factor FKHRL1 (FOXO3a), resulting in the upregulation of apoptotic protein Bim. siRNA mediated FOXO3a and Bim knockdown substantially reduced scleroderma serum-induced EPC apoptosis. Importantly, Bim expression and baseline apoptosis were increased in EPCs freshly isolated from SSc patients relative to that obtained from healthy subjects. Scleroderma serum-induced EPC apoptosis is mediated chiefly by the Akt-FOXO3a-Bim pathway, which may account, at least in part, for the decreased circulating EPC levels in SSc patients.
