CTRP3 Alleviates Ox-LDL-Induced Inflammatory Response and Endothelial Dysfunction in Mouse Aortic Endothelial Cells by Activating the PI3K/Akt/eNOS Pathway.

Abstract

C1q/tumor necrosis factor-related protein-3 (CTRP3) is a novel, certified, adipokine that beneficially regulates metabolism and inflammation in the cardiovascular system. Atherosclerotic plaque rupturing and secondary thrombosis cause vascular disorders, such as myocardial infarction and unstable angina. However, the underlying role of CTRP3 in atherosclerosis remains unclear. In this study, we aimed to elucidate whether and how CTRP3 ameliorates inflammation and endothelial dysfunction caused by oxidized low-density lipoprotein (ox-LDL). We first confirmed that CTRP3 expression was inhibited in ApoE-/- mice, compared to normal mice. Then, pcDNA-CTRP3 and siCTRP3 were transfected into mouse aortic endothelial cells after ox-LDL stimulation, and we observed that enhanced CTRP3 remarkably downregulated CRP, TNF-α, IL-6, CD40, and CD40L. We also observed that overexpression of CTRP3 elevated cell activity and decreased lactated hydrogenase release, accompanied by a marked reduction in cell apoptosis induced by ox-LDL. Meanwhile, overexpressed CTRP3 caused a decrease in Ang II, ICAM-1, and VCAM-1 expression, and it restored the balance between ET-1 and NO. Mechanism analysis confirmed that incremental CTRP3 upregulated p-PI3K, p-Akt, and p-eNOS expression, indicating that CTRP3 facilitated activation of the PI3K/Akt/eNOS pathway. On the contrary, siCTRP3 exerted the opposite effect to this activation. Blocking these pathways using LY294002 or L-NAME attenuated the protective role of CTRP3. Overall, these results suggest that CTRP3 can efficiently inhibit the inflammatory response and endothelial dysfunction induced by ox-LDL in mouse aortic endothelial cells, perhaps by activating the PI3K/Akt/eNOS pathway, indicating a promising strategy against atherosclerosis.