[Endothelin-1 production and its involvement in cardiovascular diseases]

Yakugaku Zasshi. 2007 Sep;127(9):1319-29. doi: 10.1248/yakushi.127.1319.
[Article in Japanese]

Abstract

Endothelin (ET) has been implicated in the pathogenesis of several cardiovascular disorders because of its powerful vasoconstrictor and growth-promoting properties. The ET family consists of three isoforms, ET-1, ET-2 and ET-3. ET-1 appears to be the predominant member of the family generated by vascular endothelial cells. In view of the multiple cardiovascular actions of ET-1, there has been much interest in its contribution to the pathophysiology of hypertension and arteriosclerosis. We have been investigating the roles of ET(A) and ET(B) receptors in ET-1-related cardiovascular diseases using subtype-selective ET receptor antagonists and ET(B) receptor-deficient animals. Our studies have demonstrated that ET-1 overproduction and ET(A)-mediated ET-1 actions seem to play a crucial role in the development of several types of hypertensive and post-ischemic diseases. On the other hand, ET-1 biosynthesis and release are regulated at the transcriptional level, and various endogenous substances are known to stimulate ET-1 gene expression by DNA binding of transcription factors. We and others have recently demonstrated that nuclear factor-kappaB (NF-kappaB), a transcription factor with a pivotal role in inducing genes involved in immune, inflammatory and stress responses, is responsible for endothelial ET-1 production. In in vivo studies, agents that can inhibit the NF-kappaB activation improved the development of ET-1-related cardiovascular diseases. Thus, NF-kappaB inhibition may be a pertinent treatment for ET-1 related diseases.

Publication types

  • English Abstract
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / etiology
  • Animals
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / etiology*
  • Endothelin A Receptor Antagonists
  • Endothelin-1 / biosynthesis
  • Endothelin-1 / genetics
  • Endothelin-1 / physiology*
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation
  • Humans
  • Hypertension / drug therapy
  • Hypertension / etiology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology
  • Nitric Oxide / physiology
  • Receptor, Endothelin A / physiology

Substances

  • Endothelin A Receptor Antagonists
  • Endothelin-1
  • NF-kappa B
  • Receptor, Endothelin A
  • Nitric Oxide