Role of epithelial sodium channels (ENaCs) in endothelial function

Abstract

An increasing number of mechano-sensitive ion channels in endothelial cells have been identified in response to blood flow and hydrostatic pressure. However, how these channels respond to flow under different physiological and pathological conditions remains unknown. Our results show that epithelial Na + channels (ENaCs) colocalize with hemeoxygenase-1 (HO-1) and hemeoxygenase-2 (HO-2) within the caveolae on the apical membrane of endothelial cells and are sensitive to stretch pressure and shear stress. ENaCs exhibited low levels of activity until their physiological environment was changed; in this case, the upregulation of HO-1, which in turn facilitated heme degradation and hence increased the carbon monoxide (CO) generation. CO potently increased the bioactivity of ENaCs, releasing the channel from inhibition. Endothelial cells responded to shear stress by increasing the Na + influx rate. Elevation of intracellular Na + concentration hampered the transportation of L-arginine, resulting in impaired nitric oxide (NO) generation. Our data suggest that ENaCs that are endogenous to human endothelial cells are mechano-sensitive. Persistent activation of ENaCs could inevitably lead to endothelium dysfunction and even vascular diseases such as atherosclerosis.

Activation of the Caenorhabditis elegans Degenerin Channel by Shear Stress Requires the MEC-10 Subunit

“…For example, ENaC is activated by shear stress in native kidney tubules, endothelial cells, and heterogeneous expression systems (26,41,42). ENaC gating in response to LSS was altered by mutations introduced at key sites within the large ECD and transmembrane helices (43)(44)(45)(46).…”

Oxidized low‐density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta

“…LOX‐1‐overexpressing mice fed a high‐fat diet show reduced endothelium‐dependent relaxation as a result of decreased NO availability (Eichhorn et al , ). We have shown that enhanced ENaC activity can also reduce NO production (Liu et al , ; Guo et al , ; Zheng et al , ), suggesting that ENaC can mediate ox‐LDL‐induced endothelial dysfunction. Our data presented here suggest that ox‐LDL stimulates ENaC in endothelial cells by elevating intracellular ROS and this accounts for the decreased aortic relaxation induced by ox‐LDL.…”

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels

“…More experiments by using inside-out membrane patches of HEK cells expressing ion channels may further define these two modes and enrich the interplay between iron and CO in ion channels. In the case of heme-dependent CO regulation of ion channels, if heme can be washed out from ion channels such as ENaC 76 , the potential CO effect on channel activity cannot be repeated. However, if heme cannot be washed out from ion channels such as Slo1 BK 57 Ca, the possible CO effect on channel activity may still be repeated once heme is bound.…”