We previously showed that increased epithelial sodium channel (ENaC) activity in endothelial cells induced by oxidized low-density lipoprotein (ox-LDL) contributes to vasculature dysfunction. Here, we investigated whether ENaC participates in the pathological process of atherosclerosis using LDL receptor-deficient (LDLr^−/−) mice. Male C57BL/6 and LDLr^−/− mice were fed a normal diet (ND) or high fat diet (HFD) for 10 weeks. Our data show that treatment of LDLr^−/− mice with a specific ENaC blocker, benzamil, significantly decreased atherosclerotic lesion formation and expression of matrix metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) in aortic arteries. Furthermore, benzamil ameliorated HFD-induced impairment of aortic endothelium-dependent dilation by reducing expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6 and production of adhesion molecules including VCAM-1 and ICAM-1 in both C57BL/6 and LDLr^−/− mice fed with HFD. In addition, HFD significantly increased ENaC activity and the levels of serum lipids, including ox-LDL. Our in vitro data further demonstrated that exogenous ox-LDL significantly increased the production of TNF-α, IL-1β, IL-6, VCAM-1 and ICAM-1. This ox-LDL-induced increase in inflammatory cytokines and adhesion molecules was reversed by γ-ENaC silencing or by treatment with the cyclooxygenase-2 (COX-2) antagonist celecoxib. Benzamil inhibited HFD-induced increase in COX-2 expression in aortic tissue in both C57BL/6 and LDLr^−/− mice, and γ-ENaC gene silencing attenuated ox-LDL-induced COX-2 expression in HUVECs. These data together suggest that HFD-induced activation of ENaC stimulates inflammatory signaling, thereby contributes to HFD-induced endothelial dysfunction and atherosclerotic lesion formation. Thus, targeting endothelial ENaC may be a promising strategy to halt atherogenesis.

我们以前表明，由氧化的低密度脂蛋白（ox-LDL）诱导的内皮细胞上皮钠通道（ENaC）活性增加导致脉管功能障碍。在这里，我们使用LDL受体缺陷型（LDLr ^-/-）小鼠调查了ENaC是否参与了动脉粥样硬化的病理过程。给雄性C57BL / 6和LDLr ^-/-小鼠喂食正常饮食（ND）或高脂饮食（HFD）10周。我们的数据表明对LDLr ^-/-的治疗具有特定ENaC阻断剂苯扎米尔的小鼠可显着减少主动脉中动脉粥样硬化病变的形成以及基质金属蛋白酶2（MMP2）和金属蛋白酶9（MMP9）的表达。此外，苯扎米尔通过减少两种C57BL中促炎细胞因子（包括TNF-α，IL-1β和IL-6）的表达以及包括VCAM-1和ICAM-1在内的粘附分子的产生，减轻了HFD诱导的主动脉内皮依赖性扩张的损害。 / 6和LDLr ^-/-用HFD喂养的小鼠。此外，HFD显着增加了ENaC活性和血清脂质（包括ox-LDL）的水平。我们的体外数据进一步证明，外源性ox-LDL可显着增加TNF-α，IL-1β，IL-6，VCAM-1和ICAM-1的产生。通过γ-ENaC沉默或用环氧合酶2（COX-2）拮抗剂塞来昔布治疗可逆转这种ox-LDL诱导的炎症细胞因子和粘附分子的增加。苯扎米尔抑制C57BL / 6和LDLr ^-/-中HFD诱导的主动脉组织中COX-2表达的增加小鼠和γ-ENaC基因沉默减弱了HUVEC中ox-LDL诱导的COX-2表达。这些数据共同表明，HFD诱导的ENaC激活可刺激炎症信号传导，从而促进HFD诱导的内皮功能障碍和动脉粥样硬化病变的形成。因此，靶向内皮ENaC可能是终止动脉粥样硬化的有前途的策略。