Excessive secretion of IL-8 by skeletal muscle in type 2 diabetes impairs tube growth: potential role of PI3K and the Tie2 receptor
Excessive secretion of IL-8 by skeletal muscle in type 2 diabetes impairs tube growth: potential role of PI3K and the Tie2 receptor
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DOI：
10.1152/ajpendo.00513.2014
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发表时间：
2015-07-01
影响因子：
5.1
通讯作者：
Henry, Robert R.
中科院分区：
文献类型：
--
作者：
Levy, Yifat Amir;Ciaraldi, Theodore P.;Henry, Robert R.
毛细血管密度降低是2型糖尿病（T2 D）骨骼肌（SkM）的一个特征，与多种代谢和功能异常相关。SkM已被鉴定为分泌组织，释放调节包括血管形成在内的多个过程的肌因子。我们试图确定T2 D肌管分泌的肌因子如何影响SkM血管生成。条件培养基（CM）由来自T2 D和非糖尿病（ND）受试者的肌管产生。将原代人内皮细胞（HUVEC）和SkM外植体暴露于CM或重组肌因子，并测定管数或毛细血管生长以及蛋白质表达和磷酸化的测量。来自ND肌管的CM比T2 D肌管更大程度地刺激HUVEC的管形成（48小时后，T2 D-CM = 100%，ND-CM = 288 +/- 90%，P < 0.05）。T2 D肌管CM的作用是由IL-8介导的，而不是IL-15或GRO α，并且不是由于细胞损伤，而是通过调节管的产生和维持（48小时后对T2 D-IL-8的响应= 100%，对ND-IL-8的响应= 263 +/-46%，P < 0.05）。在暴露于IL-8的SkM外植体中观察到类似的效果。IL-8对管形成的剂量依赖性作用在PI 3 K和FAK信号传导途径中也可观察到，并且至少部分由PI 3 K介导，导致Tie 2表达的调节。这些结果表明，从T2 D肌管分泌的IL-8水平升高产生了支持T2 D中毛细血管化减少的肌肉微环境。SkM血管化受损限制了底物（包括葡萄糖）的可用性，并导致T2 D表型。
Reduced capillary density is a feature of skeletal muscle (SkM) in type 2 diabetes (T2D), which is associated with multiple metabolic and functional abnormalities. SkM has been identified as a secretory tissue, releasing myokines that regulate multiple processes, including vascularization. We sought to determine how myokines secreted from T2D myotubes might influence SkM angiogenesis. Conditioned media (CM) were generated by myotubes from T2D and nondiabetic (ND) subjects. Primary human endothelial cells (HUVEC) and SkM explants were exposed to CM or recombinant myokines, and tube number or capillary outgrowth was determined as well as measurement of protein expression and phosphorylation. CM from ND myotubes stimulated tube formation of HUVEC to a greater extent than T2D myotubes (T2D-CM = 100%, ND-CM = 288 +/- 90% after 48 h, P < 0.05). The effects of T2D myotube CM were mediated by IL-8, not IL-15 or GRO alpha, and were due not to cell damage but rather through regulating tube production and maintenance (response to T2D-IL-8 = 100%, response to ND-IL-8 = 263 +/- 46% after 48 h, P < 0.05). A similar effect was seen in SkM explants with exposure to IL-8. The dose-dependent effect of IL-8 on tube formation was also observable in the PI3K and FAK signaling pathways and mediated at least in part by PI3K, leading to regulation of Tie2 expression. These results suggest that elevated levels of IL-8 secreted from T2D myotubes create a muscle microenvironment that supports reduced capillarization in T2D. Impaired vascularization of SkM limits the availability of substrates, including glucose and contributes to the T2D phenotype.