Regulation of endothelin-1 production by a thromboxane A2 mimetic in rat heart smooth muscle cells.
Thromboxane A2 (TXA2) and ET-1 have been known to play important roles in modulating vascular contraction and growth. The present study was undertaken to examine the effect of TXA2 on the induction of endothelin-1 (ET-1) mRNA and protein levels in smooth muscle cells derived from rat heart. U-46619, a stable TXA2 mimetic, superinduced preproET-1 mRNA in the presence of cycloheximide in these cells. This effect could be blocked by SQ-29548, a TXA2/prostaglandin H2 receptor antagonist and by actinomycin D, and RNA synthesis inhibitor. In addition, H7, a protein kinase C inhibitor, could abolish the induction. Transient transfection experiment revealed that the elevated ET-1 mRNA level after U-46619 treatment was a result of the activation of ET-1 gene activity. The elevated ET-1 message level was accompanied by increased ET-1 release into the cultured medium. These results show that the short-lived TXA2 can induce potent and long-lived ET-1. These findings support a potential role for ET-1 in the pathogenesis of coronary atherosclerosis and hypertension evoked by TXA2.
Chua
C C
CC
Division of Geriatric Medicine, James Quillen School of Medicine, East Tennessee State University, Johnson City, USA.
Hamdy
R C
RC
Chua
B H
BH
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D016232:Endothelins / Q000096:biosynthesis* / Q000235:genetics; D005231:Fatty Acids, Unsaturated; D015870:Gene Expression / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000502:physiology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007546:Isoquinolines; D010879:Piperazines; D011450:Prostaglandin Endoperoxides, Synthetic; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C045749:SQ 29548; D011493:Protein Kinase C