CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis. (November 2018)

• Record Type: Journal Article
• Authors: Li, Chang; Chen, Jia Wei; Liu, Zhu Hui; Shen, Ying; Ding, Feng Hua; Gu, Gang; Liu, Jun; Qiu, Jia Pei; Gao, Jie; Zhang, Rui Yan; Shen, Wei Feng; Wang, Xiao Qun; Lu, Lin
• Is Part Of: Atherosclerosis. Volume 278(2018)
• Page Start: 197
• Page End: 209
• Publication Date: 2018-11
• Subjects: CTRP5 -- Endothelial cells -- Transcytosis -- 12/15-Lipoxygenase -- Low-density lipoprotein; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.09.037
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined. Methods: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo . Results: We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ± 61.71 vs. 167.81 ± 68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis. Conclusions: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX. Highlights: CTRP5 is elevated in sera of patients with than without CAD and correlates with the severity of atherosclerosis. CTRP5 expression is increased in atherosclerotic plaques and localized in endothelial cells, infiltrated macrophages, and smooth muscle cells in the neointima. CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein in the subendothelial space through a STAT6-12/15-lipoxygenase-dependent pathway. Inhibition of 12/15-lipoxygenase attenuates CTRP5-induced transcytosis and oxidation of LDL and atherogenesis.