Linking regulation of nitric oxide to endothelin-1: The Yin and Yang of vascular tone in the atherosclerotic plaque

Abstract

A healthy endothelium prevents the development of atherosclerosis through protective effects on vasomotion, platelet adhesion, leukocyte trafficking, anti-inflammatory and anti-oxidant properties [ [1] Gimbrone M.A. Garcia-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ. Res. 2016; 118: 620-636https://doi.org/10.1161/CIRCRESAHA.115.306301 Crossref PubMed Scopus (1612) Google Scholar ]. Nitric oxide and endothelin-1, autocrine and paracrine factors produced by endothelial cells, have opposing effects on smooth muscle cells contraction. The net balance between these pleiotropic molecules contributes to the regulation of local vascular tone. Nitric oxide (NO), the most potent vasodilatory molecule produced in the arterial wall, mediates endothelium-dependent relaxation (EDR). NO arises from the conversion of l-arginine to l-citrulline by the enzymatic action of an NADPH-dependent NO synthase (NOS) [ [2] Vanhoutte P.M. Zhao Y. Xu A. Leung S.W.S. Thirty years of saying NO: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circ. Res. 2016; 119: 375-396https://doi.org/10.1161/CIRCRESAHA.116.306531 Crossref PubMed Scopus (251) Google Scholar ]. The endothelium produces NO by constitutive expression of the endothelial isoform of NOS (NOS3), which is activated by shear stress [ [3] Harrison D.G. Cellular and molecular mechanisms of endothelial cell dysfunction. J. Clin. Investig. 1997; 100: 2153-2157https://doi.org/10.1172/JCI119751 Crossref PubMed Scopus (898) Google Scholar ]. NO has a variety of functions, but its action as the predominant endothelium-derived relaxing factor (EDRF) is the most important for the maintenance of vascular homeostasis. Endothelin-1 (ET-1), which is encoded by the preproendothelin-1 gene (EDN1), functions as an opposing force on vascular tone, mediating vasoconstriction of vascular smooth muscle cells through binding to endothelin ETA receptors [ [4] Barton M. Yanagisawa M. Endothelin: 30 years from discovery to therapy. Hypertension. 2019; 74: 1232-1265https://doi.org/10.1161/HYPERTENSIONAHA.119.12105 Crossref PubMed Scopus (90) Google Scholar ]. ET-1 links causally to coronary artery disease. ETA receptor (EDNRA) blockade inhibits whereas endothelium-restricted overexpression of EDN1 increases experimental atherosclerosis in mice [ [5] Li M.W. Mian M.O.R. Barhoumi T. Rehman A. Mann K. et al. Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 2013; 33: 2306-2315https://doi.org/10.1161/ATVBAHA.113.302028 Crossref PubMed Scopus (79) Google Scholar , [6] Barton M. Haudenschild C.C. d’Uscio L.V. Shaw S. Münter K. Lüscher T.F. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14367-14372https://doi.org/10.1073/pnas.95.24.14367 Crossref PubMed Scopus (335) Google Scholar ], and non-coding variants that regulate EDN1 and EDNRA expression associate with human disease in genome-wide associate studies [ [7] Gupta R.M. Hadaya J. Trehan A. Zekavat S.M. Roselli C. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression,. Cell. 2017; 170 (e15): 522-533https://doi.org/10.1016/j.cell.2017.06.049 Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar , [8] Nikpay M. Goel A. Won H.-H. Hall L.M. Willenborg C. et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease,. Nat. Genet. 2015; 47: 1121-1130https://doi.org/10.1038/ng.3396 Crossref PubMed Scopus (1323) Google Scholar ]. Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaquesAtherosclerosisVol. 292PreviewEndothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages. Full-Text PDF