Subject of Review: 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 the PHACTR1 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. Second Opinion: However, ET-1 has been demonstrated to play a role in experimental and human hypertension. How can enhanced transcription of EDN1 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. Conclusion: 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 the PHACTR1 gene that is a distal regulator of EDN1 and leads to an increased expression of ET-1.

Keywords:
Arterial hypertension, Endothelin, Endothelium, Gene polymorphism
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2018
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