Abstract
Previous studies have shown that high salt induces artery stiffness by causing endothelial dysfunction via increased sodium influx. We used our unique split-open artery technique combined with protein biochemistry and in vitro measurement of vascular tone to test a hypothesis that bone morphogenetic protein 4 (BMP4) mediates high salt-induced loss of vascular relaxation by stimulating the epithelial sodium channel (ENaC) in endothelial cells. The data show that high salt intake increased BMP4 both in endothelial cells and in the serum and that exogenous BMP4 stimulated ENaC in endothelial cells. The data also show that the stimulation is mediated by p38 mitogen-activated protein kinases (p38 MAPK) and serum and glucocorticoid-regulated kinase 1 (Sgk1)/neural precursor cell expressed developmentally downregulated gene 4-2 (Nedd4-2) (Sgk1/Nedd4-2). Furthermore, BMP4 decreased mesenteric artery relaxation in a benzamil-sensitive manner. These results suggest that high salt intake stimulates endothelial cells to express and release BMP4 and that the released BMP4 reduces artery relaxation by stimulating ENaC in endothelial cells. Therefore, stimulation of ENaC in endothelial cells by BMP4 may serve as another pathway to participate in the complex mechanism of salt-sensitive (SS) hypertension.
Highlights
High dietary sodium chloride intake has been related to hypertension and its target organ damage [1]
Our data showed that the expression levels of p-p38 MAPK but not those of p38 MAPK were significantly elevated in endothelial cells from HS diet-fed SS rats, but not in those from normal salt (NS) diet-fed SS rats (Figures 4(a) and 4(b))
The results showed that HS diet-induced impairment of Endothelium-dependent relaxation (EDR) was reversed by treating the vascular rings with a p38 MAPK inhibitor, SB202190 (20 μM) for 4 hours in SS rats (Figures 4(c)–4(e))
Summary
High dietary sodium chloride intake has been related to hypertension and its target organ damage [1]. High salt-induced endothelial cell stiffness promotes increased arterial stiffness by elevating transforming growth factor (TGF)-β levels [3]. Recent clinical studies have shown that high salt intake induces large artery stiffness in a salt-sensitive population [4]. Investigation of the molecular mechanism by which high salt causes endothelial cell dysfunction and artery stiffness has clinical significance for improving the management of saltsensitive hypertension. Previous studies have shown that elevated sodium influx accounts for endothelial cell stiffness [5]. The pathways for sodium influx were unclear, until we recently recorded the single-channel activity of ENaC in endothelial cells [6]. The complex mechanism by which high dietary salt stimulates ENaC in endothelial cells remains to be further determined
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