Oxidized LDL (ox-LDL) is the key risk factor of developing atherosclerosis. In endothelial cells, exposure of ox-LDL causes endothelial dysfunction and injury. In this study, we investigated the role of receptor interacting protein 1 (RIP1), one of the kinases involved in apoptosis and necroptosis mediated by the death receptor tumor necrosis factor receptor (TNFR), in endothelial dysfunction. We show that RIP1 is responsively induced in human umbilical vein endothelial cells (HUVECs) upon ox-LDL treatment. Blockage of RIP1 activity by its antagonist, necrostatin-1, ameliorates ox-LDL-induced nitric oxide (NO) reduction and induction of vascular adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, as well as adhesion of immune cells to endothelial cells. Mechanistically, we show that inactivation of RIP1 by necrostatin-1 suppressed nuclear factor kappa B (NF-kappa B) cascade signals, including activation of IKK alpha, nuclear factor kappa B inhibitor protein alpha (I kappa B alpha), accumulation of nuclear p65 and NF-kappa B promoter activity. Silencing of RIP1 largely attenuates the action of ox-LDL on the expression of vascular adhesion molecules and adhesion of immune cells to endothelial cells. Collectively, our data indicate that the response of RIP1 to ox-LDL and its activation are required for ox-LDL-induced endothelial injury.
[1]Fudan Univ, Zhongshan Hosp, Dept Cardiol, Shanghai, Peoples R China;
[2]Zhengzhou Univ, Dept Cardiol, Peoples Hosp, Zhengzhou 450003, Henan, Peoples R China;
[3]Jilin Univ, Hosp 1, Dept Cardiol, Changchun 130021, Jilin, Peoples R China
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