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High salt diet (HSD) contributed to the development of cardiovascular diseases (CVDs), however, with the mechanisms remained elusive. It was found that HSD promoted inflammatory responses including cardiovascular inflammation in vivo, and inflammation drove CVDs’ development. HSD-induced inflammation was closely associated with high Nacl resulted from HSD. HSD-induced cardiovascular inflammation might be regulated by pro-inflammatory endothelial cells (ECs). The expression of adhesion molecules including VCAM-1, which mediates leucocytes infiltration, underlies the pro-inflammatory ECs. VCAM-1 was important for the initiation of atherosclerosis, a common inflammatory CVD. The present study was aimed to determine whether high Nacl and HSD could induce VCAM-1 expression in vivo and in vitro, as well as its related mechanisms.
Human ECs were exposed to high Nacl, and VCAM-1 expression was examined. Na+ and Cl- were substituted for NMDG+ and gluconate with mannitol as isotonic control in order to determine which part was critical for VCAM-1 induction. Then its associated signaling pathway was studied by means of specific inhibitors. In vivo, SD rats were fed with HSD or normal salt diet (NSD), and aorta intima was collected followed by investigation of VCAM-1 expression and the related signaling molecules activation.
High Nacl remarkably upregulated VCAM-1 expression in ECs, which was dependent on high Cl- but not high Na+ or osmolality. PI3K/ AKT/ GSK3β/ IκBα/ NFκB pathway activation mediated high Nacl-induced VCAM-1 expression. Meanwhile, HSD promoted VCAM-1 expression and the above mentioned signaling molecules activation in aorta intima of SD rats in comparison of NSD. Bumetanide as the specific inhibitor for Na-K-Cl cotransporter (NKCC-1) significantly suppressed high Nacl-induced PI3K/ AKT/ GSK3β/ IκBα/ NFκB pathway activation and VCAM-1 expression.
High Cl- activated PI3K/ AKT/ GSK3β/ IκBα/ NFκB pathway via NKCC-1, thereby promoting VCAM-1 expression in high Nacl-stimulated ECs. NKCC-1 might be a feasible target in HSD-associated CVDs intervention.