Selenoprotein S protects against high glucose-induced vascular endothelial apoptosis through the PKCbetaII/JNK/Bcl-2 pathway.
Selenoprotein S protects against high glucose-induced vascular endothelial apoptosis through the PKCbetaII/JNK/Bcl-2 pathway.
复制标题
硒蛋白 S 通过 PKCbetaII/JNK/Bcl-2 途径防止高葡萄糖诱导的血管内皮细胞凋亡。
DOI：
10.1002/jcb.28154
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发表时间：
2018
影响因子：
4
通讯作者：
Du Jianling
中科院分区：
文献类型：
--
作者：
Yu Shanshan;Liu Xiaoying;Men Lili;Yao Junjie;Xing Qian;Du Jianling
血管内皮细胞凋亡与糖尿病大血管病变的发生、发展密切相关。硒蛋白S（SelS）参与保护血管内皮细胞和平滑肌细胞免受氧化和内质网应激诱导的损伤。然而，SelS是否可以保护血管内皮免受高糖（HG）诱导的凋亡及其机制尚不清楚。本研究初步分析了在体糖尿病大鼠主动脉内皮细胞凋亡及SelS表达的变化，以及HG对体外培养的人脐静脉内皮细胞（HUVEC）凋亡及SelS表达的影响。随后，利用pcDNA3.1-SelS重组质粒和SelS特异性小干扰RNA上调或下调HUVEC中SelS的表达，分析SelS高/低表达对HG诱导HUVEC凋亡的影响及其可能的分子机制。正如预期的那样，HG在体内和体外诱导血管内皮细胞凋亡和上调内皮细胞SelS表达。HUVEC中SelS过表达抑制HG诱导的细胞凋亡和切割caspase 3水平的增加，伴随着蛋白激酶CβII（PKCβII）、c-JUN N-末端激酶（JNK）和B-细胞淋巴瘤/白血病-2（Bcl-2）磷酸化的减少。相反，抑制HUVECs中SelS的表达进一步加重HG诱导的细胞凋亡和切割的caspase 3水平的增加，这伴随着PKCβII、JNK和Bcl-2磷酸化的增加。用PKC激活剂预处理可阻断SelS的保护作用，并增加HUVECs的凋亡和切割的caspase 3水平。总之，SelS保护血管内皮免受HG诱导的细胞凋亡，这是通过抑制PKCβII/JNK/Bcl-2通路最终抑制caspase 3激活来实现的。SelS可能是预防和治疗糖尿病大血管并发症的一个有希望的靶点。
Vascular endothelial apoptosis is closely associated with the pathogenesis and progression of diabetic macrovascular diseases. Selenoprotein S (SelS) participates in the protection of vascular endothelial and smooth muscle cells from oxidative and endoplasmic reticulum stress‐induced injury. However, whether SelS can protect vascular endothelium from high glucose (HG)‐induced apoptosis and the underlying mechanism remains unclear. The present study preliminarily analyzed aortic endothelial apoptosis and SelS expression in diabetic rats in vivo and the effects of HG on human umbilical vein endothelial cell (HUVEC) apoptosis and SelS expression in vitro. Subsequently, SelS expression was up‐ or downregulated in HUVECs using the pcDNA3.1‐SelS recombinant plasmid and SelS‐specific small interfering RNAs, and the effects of high/low SelS expression on HG‐induced HUVEC apoptosis and a possible molecular mechanism were analyzed. As expected, HG induced vascular endothelial apoptosis and upregulated endothelial SelS expression in vivo and in vitro. SelS overexpression in HUVECs suppressed HG‐induced increase in apoptosis and cleaved caspase3 level, accompanied by reduced protein kinase CβII (PKCβII), c‐JUN N‐terminal kinase (JNK), and B‐cell lymphoma/leukemia‐2 (Bcl‐2) phosphorylation. In contrast, inhibiting SelS expression in HUVECs further aggravated HG‐induced increase in apoptosis and cleaved caspase3 level, which was accompanied by increased PKCβII, JNK, and Bcl‐2 phosphorylation. Pretreatment with PKC activators blocked the protective effects of SelS and increased the apoptosis and cleaved caspase3 level in HUVECs. In summary, SelS protects vascular endothelium from HG‐induced apoptosis, and this was achieved through the inhibition of PKCβII/JNK/Bcl‐2 pathway to eventually inhibit caspase3 activation. SelS may be a promising target for the prevention and treatment of diabetic macrovascular complications.