Key result
Dilazep potently inhibited preproendothelin-1 gene transcription in serum-treated endothelial cells at 24 hours (0.04 vs 1, p<0.0001) and suppressed ET-1 promoter activity by 99% (p<0.01).
Why the study?
Does dilazep inhibit endothelin-1 gene expression in cultured endothelial cells?
Does dilazep inhibit endothelin-1 gene expression in cultured endothelial cells?
Dilazep potently inhibits endothelin-1 gene expression at the transcriptional level in cultured endothelial cells, providing a potential mechanism for its cardiovascular and renal protective effects.
Dilazep's ET-1 transcriptional inhibition in vitro is hypothesis-generating; leaves open any clinical role pending in vivo confirmation.
Endothelin-1 (ET-1) is considered to be involved in various cardiovascular and renal disorders. The objective of this study was to investigate whether a vasodilator and antiplatelet agent, 1,4-bis[3-(3,4,5-trimethoxybenzoyloxy) propyl]perhydro-1,4-diazepine dihydrochloride monohydrate (dilazep, DZ), has an ET-1-inhibiting effect in vitro. Bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) pretreated with fetal calf serum were treated with DZ and preproET-1 (PpET-1) transcription was evaluated by Northern blot analysis. ET-1 peptide release in culture medium was evaluated by radioimmunoassay. The effect of DZ on the ET-1 promoter/enhancer apparatus was evaluated in transfection experiments using -5 kb ET-1 promoter/enhancer constructs. Modest inhibition of PpET-1 gene transcription was detected after 30 min of DZ treatment (0.56+/-0.19 vs. 1 , p<0.01) and more marked inhibition was seen at 24 h (0.04+/-0.04 vs. 1, p<0.0001). ET-1 peptide release was suppressed strongly after 3 h (382.5+/-2.9 vs. 673.5+/-74.5pg/ml, p< 0.001) and 24 h (38.8+/-9.8 vs. 5,075+/-52.0pg/ml, p<0.0001). DZ potently inhibited PpET-1 transcription in a concentration-dependent manner (0.42+/-0.18 vs. 1, p<0.001, at 100micromol/l). DZ suppressed PpET-1 transcription in confluent HUVEC at 3 h (0.41 +/-0.11 vs. 1, p<0.0001). DZ strongly inhibited PpET-1 transcription after 1 h of thrombin (TH) treatment (0.30+/-0.01 vs. 1.51+/-0.03, p<0.0001). Transfection experiments using the 5 kb ET-1 promoter-luciferase plasmid revealed that DZ strongly suppressed ET-1 promoter activity by 99% (p<0.01). DZ potently inhibited ET-1 gene expression at the transcription level in serum- or TH-treated endothelial cells.
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Shrestha et al. (2004) studied Endothelial cell function (in vitro). Dilazep vs. Control (serum-treated cells without dilazep) was evaluated on Preproendothelin-1 (PpET-1) gene transcription at 24 hours (p=<0.0001). Dilazep potently inhibited preproendothelin-1 gene transcription in serum-treated endothelial cells at 24 hours (0.04 vs 1, p<0.0001) and suppressed ET-1 promoter activity by 99% (p<0.01).
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