内皮功能障碍和损伤是血管性疾病的早期事件和始动因素。研究显示：内皮中的上皮细胞钠通道（ENaC）对调节血管功能具有重要作用。我们发现：高盐摄入/脂代谢紊乱导致的内皮ENaC表达/活性升高与内皮和血管功能障碍密切相关；然而，其分子机制及调控网络不明。基于已发表和本课题的前期研究结果，我们假设：高盐摄入/脂代谢紊乱通过显著上调内皮ENaC表达和持续激活ENaC，导致内皮中[Na+]显著升高，而使eNOS活性及NO合成降低，最终导致血管功能紊乱和血管重构。我们将应用野生型及疾病模式动物，结合多种研究方法，阐明ENaC在血管稳态中的作用，揭示高盐摄入/脂代谢紊乱导致内皮ENaC表达/活性升高、从而导致血管稳态失衡及血管重构的关键信号分子及节点；揭示小分子气体NO、H2S和他汀类药物如何通过抑制ENaC而显著减轻/延缓血管稳态失衡及结构重构，为血管功能紊乱和血管重构的早期干预提供新的靶点和干预手段。

Dysfunction and/or injury of endothelium lead to imbalance of vascular homeostasis and to vascular remodeling, which also promote the incidence of cardiovascular diseases. The data shown by us and others indicate that epithelial sodium channel (ENaC) is expressed in vascular endothelial cells and that ENaC plays an important role in regulation of endothelium function. Our preliminary results suggest that the activity and expression levels of ENaC in rat mesenteric artery endothelial cells can be strongly stimulated by high salt diet. Alteration of ENaC activity and its expression contribute to reduced eNOS activity and NO production, as well as to the altered endothelial-dependent vascular relaxation. Our data also show that ENaC in mouse endothelial cells of thoracic aorta is stimulated by ox-LDL, an oxidized isoform of LDL. Based upon our previously published results and the preliminary data shown in this application, we hypothesize that both high salt and lipid metabolic disorder stimulate expression and activity of ENaC via oxidative stress and intracellular signaling and molecules, and subsequently causes dysfunction of endothelium, imbalance of vascular homeostasis and vascular remodeling; NO/H2S and Lovastatin may prevent high salt or lipid-metabolic disorder-induced endothelial dysfunction through inhibition of ENaC. We will use Dah1/Rapp salt-sensitive (SS) and Sprague-Dawley rats (SD), C57BL/6J and LDLr-/- mice, the primary cultured endothelial cells isolated from the animal models as described above, as well as HUVEC cell line combined with electrophysiological recordings in split-open arteries, molecular biology, imaging analysis, and wire myograph analysis to address our hypothesis. We will demonstrate the role of ENaC in maintaining the vascular homeostasis; we will determine whether high salt and disorder of lipid metabolism regulate ENaC and the mechanisms by which high salt and disorder of lipid metabolism-induced ENaC upregulation contribute to dysfunction of endothelium and the development of vascular dysfunction and remodeling; we will test whether NO/H2S donor and Lovastatin exert a protective effects on pathophysiological processes through inhibition of ENaC. The results obtained by proposed studies will gain our knowledge in understanding the molecular basis and mechanisms of vascular dysfunction and remodeling. Our results may provide rational for preventing and curing the cardiovascular diseases.