HomeoboxC6 affects the apoptosis of human vascular endothelial cells and is involved in atherosclerosis

Abstract

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.

Potential miRNA biomarkers and therapeutic targets for early atherosclerotic lesions

“…For example, BCL2, encodes an outer mitochondrial membrane protein that is anti-apoptotic. The molecule is downregulated in aortic atherosclerotic lesions in rats 49 . VEGFA is a growth factor that induces proliferation and migration of vascular endothelial cells, and is essential for both physiological and pathological angiogenesis, resulting in plaque neovascularization, increased microvessel permeability, and intraplaque hemorrhage 50 , 51 .…”

Deciphering the emerging landscape of HOX genes in cardiovascular biology, atherosclerosis and beyond (Review)

“…Therefore, ECs have crucial roles in atherosclerosis initiation and progression. A previous study by our group suggested that HOXC6 knockdown leads to blunted apoptosis of VECs ( 59 ), and further mechanistic study showed that HOXC6 exerts its function through the phospholipase Cβ/protein kinase Cζ/NF-кB/IL-18 signaling pathway ( 59 ). HOXA1 expression is upregulated in patients with atherosclerosis.…”

lncRNA HOTAIRM1 Activated by HOXA4 Drives HUVEC Proliferation Through Direct Interaction with Protein Partner HSPA5

“…VECs are one of the primary cellular constituents of the blood vessel wall, and the destruction of their integrity is a pivotal factor in AS pathogenesis [ 5 ]. The dynamic equilibrium between VEC proliferation and apoptosis is the key cytological basis for maintaining VEC integrity and ensuring normal vascular function [ 6 ]. Thus, interrogating novel molecules affecting the proliferation and apoptosis of VEC is important in AS.…”