[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.
Ohkita
Mamoru
M
Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki City, Japan.
Takaoka
Masanori
M
Matsumura
Yasuo
Y
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D044022:Receptor, Endothelin A / Q000502:physiology