PMID: 8587330Jan 1, 1995Paper

Thrombin-mediated ET-1 gene regulation involves CaM kinases and calcineurin in human endothelial cells

Journal of Cardiovascular Pharmacology
T A MarsenM J Dunn

Abstract

The preproendothelin-1 (preproET-1) gene is induced by thrombin after phosphorylation of nonreceptor protein tyrosine kinase pathways. This study investigated the contribution of Ca2+/calmodulin-dependent intracellular signaling cascades to this pathway and measured ET-1 mRNA levels by Northern blot analysis in human endothelial cells. Increased intracellular Ca2+ levels in response to Ca2+ ionophore or Ca2+ ATPase inhibitors tert-butylhydroquinone and thapsigargin mimicked thrombin actions on ET-1 mRNA induction. Thrombin-mediated activation of ET-1 mRNA was reduced by specific calmodulin antagonists W7 or calmidazolium and after inhibition of CaM kinase II by KN-62. Inhibition of calcium/calmodulin-dependent phosphatase calcineurin by cyclosporin A, however, stimulated ET-1 mRNA in human endothelial cells. Phosphotyrosine immunoblot assays show that calcium/calmodulin-dependent signaling pathways precede thrombin-induced tyrosine phosphorylation, and that the calcium/calmodulin-dependent phosphatase calcineurin also exerts its effects via activation of protein tyrosine kinases. These observations demonstrate that thrombin stimulates the preproET-1 gene in human endothelial cells through calcium-dependent activation of CaM kin...Continue Reading

Citations

Sep 28, 1999·European Journal of Pharmacology·T A MarsenC A Baldamus
Dec 13, 2001·Neurochemistry International·María del Carmen Boyano-Adánez, Lena Gustavsson
May 16, 2003·Vascular Pharmacology·Natalia V BogatchevaAlexander D Verin
Oct 13, 2000·Fundamental & Clinical Pharmacology·T A MarsenC A Baldamus
Jun 6, 1998·Proceedings of the National Academy of Sciences of the United States of America·M IsshikiA Kamiya
Apr 29, 2000·Current Opinion in Urology·A R Rosenkranz, G Mayer

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