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

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.