The matricellular protein CCN1 regulates TNF-alpha induced vascular endothelial cell apoptosis

摘要

Due to the epidemic obesity and associated diabetes, the incidence of atherosclerosis is increasing worldwide. Atherosclerosis is a chronic inflammatory disease characterized by the hardening and narrowing of arteries with plaques that consist of inflammatory cells, dead endothelial cells, lipids, and often hyper proliferated vascular smooth muscle cells. During the development of atherosclerosis, vascular endothelial cell (EC) apoptosis induced by the adipokine tumor necrosis factor alpha (TNF-alpha) is an early event in the plaque formation. However, TNF-alpha alone is not sufficient to induce apoptosis of endothelial cells. Recent studies suggested that the matricellular protein CCN family member 1 (CCN1) involves in endothelial cell dysfunction besides its well-known angiogenic function during tissue repair by promoting vascular smooth muscle cells proliferation and migration. Herein, we explored the possibility and mechanism of CCN1 in TNF-a induced endothelial cells apoptosis. Both mRNA and protein levels of CCN1 are found up-regulated in endothelial cells after TNF-a treatment. In addition, overexpression of CCN1 promoted endothelial cell apoptosis in the presence of TNF-alpha. Furthermore, CCN1 directly up-regulated the expression of TNF-a-target genes, and this up-regulation required the activation of P53 and NF-kappa B both in vivo and in vitro. Taken together, CNN1 regulates TNF-alpha induced endothelial cells apoptosis that may underlie poor response to TNF-alpha therapy and hence may be a better therapeutic target for preventing vascular dysfunction in obesity.