Medical College, Guizhou University, Guiyang, Guizhou, China.
Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
J Cell Physiol. 2021 Mar;236(3):1913-1925. doi: 10.1002/jcp.29974. Epub 2020 Aug 1.
Apoptosis of vascular endothelial cells (VECs) is highly important in the occurrence and development of atherosclerosis (AS). HomeboxC6 (HOXC6) is expressed in higher levels in multiple malignant tissues, and it influences the malignant biological behavior of the cancer cells. However, the effects of HOXC6 on AS and the apoptosis of VECs have not been fully elucidated. In this study, we demonstrated that HOXC6 expression was increased in aortic wall of AS rats and peripheral blood monocytes of patients with coronary heart disease. Furthermore, it was uncovered that BAX expression was upregulated, while BCL-2 expression was downregulated in the aortic wall of AS rats. The apoptosis of human VECs (HVECs) cultured normally or treated with oxidized low-density lipoprotein in vitro was decreased after transfection with HOXC6-siRNA. Moreover, the results of Western blot analysis unveiled that the expressions of proapoptotic proteins, such as BAX, caspase-3, cleaved-caspase-3, and caspase-9 were reduced, while the expression of antiapoptotic protein, BCL-2, was elevated. Meanwhile, mRNA and protein expressions of phospholipase C beta (PLCβ) were decreased, the phosphorylation levels of protein kinase C zeta (PKCζ) and nuclear transcription factor-κB-p65 (NF-κBp65) and the membrane translocation of PKCζ were reduced as well. Besides, the expression of interleukin-18 (IL-18) protein was downregulated. However, after overexpression of HOXC6, the opposite trends of the abovementioned indices were observed. Furthermore, the inhibition of apoptosis induced by HOXC6-siRNA was reversed by lysophosphatidylcholine, an activator of PKCζ. Taken together, our results indicated that HOXC6 can promote the apoptosis of HVECs and may be involved in the occurrence and development of AS, which may be partially associated with the activation of PLCβ/PKCζ/NF-κBp65/IL-18 signaling pathway.
血管内皮细胞（VECs）的凋亡在动脉粥样硬化（AS）的发生和发展中至关重要。同源盒 C6（HOXC6）在多种恶性组织中表达水平较高，它影响癌细胞的恶性生物学行为。然而，HOXC6 对 AS 和 VEC 凋亡的影响尚未完全阐明。在这项研究中，我们证明了 AS 大鼠主动脉壁和冠心病患者外周血单核细胞中 HOXC6 的表达增加。此外，我们发现 AS 大鼠主动脉壁中 BAX 表达上调，BCL-2 表达下调。转染 HOXC6-siRNA 后，体外培养的人血管内皮细胞（HVEC）或经氧化低密度脂蛋白处理的 HVEC 凋亡减少。此外，Western blot 分析结果显示，促凋亡蛋白如 BAX、caspase-3、cleaved-caspase-3 和 caspase-9 的表达减少，而抗凋亡蛋白 BCL-2 的表达增加。同时，磷脂酶 Cβ（PLCβ）的 mRNA 和蛋白表达减少，蛋白激酶 C ζ（PKCζ）和核转录因子-κB-p65（NF-κBp65）的磷酸化水平以及 PKCζ 的核膜转位减少，白细胞介素-18（IL-18）蛋白的表达也下调。然而，过表达 HOXC6 后，上述指标的趋势相反。此外，HOXC6-siRNA 诱导的凋亡抑制被 PKCζ 的激活剂溶血磷脂酰胆碱逆转。综上所述，我们的研究结果表明，HOXC6 可以促进 HVEC 凋亡，可能参与 AS 的发生和发展，这可能与 PLCβ/PKCζ/NF-κBp65/IL-18 信号通路的激活有关。
