Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction

作者：Kawakami Akio^*; Osaka Mizuko; Tani Mariko; Azuma Hiroshi; Sacks Frank M; Shimokado Kentaro; Yoshida Masayuki

来源：Circulation, 2008, 118(7): 731-742.

DOI：10.1161/CIRCULATIONAHA.108.784785

• apolipoproteins
• endothelium
• hyperlipoproteinemia
• insulin
• nitric oxide synthase

Background-Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-beta (PKC beta). Because PKC beta impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo.
Methods and Results-ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKC beta in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKC beta. The impaired insulin signaling was restored by PKC beta inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKC beta inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKC beta, which inhibits the IRS-1/PI3K/Akt/eNOS pathway.
Conclusion-Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.

• 出版日期2008-8-12