A Genetic Variant Associated with the Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Gupta et al. [Cell 2017; 170: 522 –533] have shown that a genetic variant associated with the 5 vascular diseases is a distal regulator of endothelin (ET)-1 gene (EDN1) expression. A common single nucleotide polymorphism (SNP) in the third intron of thePHACTR1 gene, rs9349379, is the potential variant responsible for increased risk of coronary artery disease, and lower risk of migraine, carotid dissection, fibromuscular dysplasia, and hypertension. Since ET-1 acts through ET type B receptors (ETBR) on endothelial cells to stimulate the production of nitric oxide and prostacyclin and induce vasodilation, this may contribute to these findings. However, ET-1 has been demonstrated to play a role in experimental and human hypertension. How can enhanced transcription ofEDN1 and translation leading to increased production of ET-1 by endothelial cells play a role in hypertension despite the availability of data that suggest a hypotensive action of ET-1? This could depend on the genetic background of individuals. In some humans, the increased ET-1 vasoconstrictor action on ETAR and ETBR in vascular smooth muscle might predominate over the vasodilator effects exerted via endothelial ETBR, thus resulting in elevated blood pressure. Alternatively, hypertension could be attributed to renal actions of ET-1. Either of these pathophysiological actions may explain a hypertensive role of ET-1 despite a lower risk of hypertension associated with the G allele at rs9349379, the common SNP in th...
Source: Nephron - Category: Urology & Nephrology Source Type: research