Changes of plasma endothelin and growth factor levels, and of left ventricular mass, after chronic AT1-receptor blockade in human hypertension.
ABSTRACT The stimulation of autocrine and paracrine factors such as basic fibroblast- (bFGF) and platelet-derived (PDGF) growth factors mediates many of the growth-promoting actions of angiotensin II. The aim of this study was to evaluate the effect of chronic AT1-receptor blockade on plasma endothelin-1 (ET-1) and growth factors levels, and on left ventricular mass, in essential hypertension (EH). The study population consisted of 16 patients with mild-moderate EH, and 25 normotensive controls. In the EH patients under basal conditions, and after 3 and 6 months of chronic therapy with Losartan 50 mg/day, we measured serum levels of ET-1, bFGF and PDGF, and tumor necrosis factor (TNF). At the same time, all patients underwent 24-h ambulatory blood pressure monitoring and an echocardiographic evaluation to measure the thickness of the posterior wall (PWT) of the left ventricle and of the interventricular septum (IVS). The healthy controls underwent the same analyses, under basal conditions, at baseline and after 3 and 6 months of observation. In the EH patients, after 3 months of AT1-receptor blockade bFGF was reduced from 13.6 +/- 0.7 to 10.9 +/- 0.7 pg/mL (P < .004), and both TNF and PDGF were significantly decreased (P < .006 and P < .007, respectively). After 6 months of therapy, ET-1 was significantly diminished in comparison with baseline (6.9 +/- 0.8 v 5.5 +/- 0.1 fmol/mL; P < .05), and the reduction in the levels of growth factors were even more significant than at 3 months of treatment. Both PWT and IVS were significantly changed after 6 months of therapy with losartan after basal evaluation (P < .05, respectively). Systolic and diastolic 24-h blood pressures declined significantly after 3 and 6 months of therapy with losartan (P < .01, respectively). It seems likely that the inhibition of the action of angiotensin II by the specific AT1-receptor blockade, by reducing circulating levels of ET-1 and those of some growth factors, may offer an advantage regarding the effect on hypertensive cardiovascular changes in human hypertension.
- SourceAvailable from: Adel M Malek[show abstract] [hide abstract]
ABSTRACT: Fluid shear stress induces a number of morphological and functional changes in vascular endothelium, including a rapid and significant down-regulation of endothelin 1 (ET-1) mRNA and peptide release in bovine aortic endothelial cells. We show here that both the cell alignment and ET-1 down-regulation depend on on-going protein synthesis, and that the latter is the result of a decrease in transcription, as shown by nuclear run-off assay, and not the result of changes in ET-1 mRNA half-life. The treatment of endothelial cells with either phorbol 12-myristate 13-acetate (100 nM) to activate protein kinase C (PKC) or forskolin (10 microM) to stimulate adenylate cyclase sharply decreased ET-1 mRNA. However, the phorbol-induced ET-1 decrease was, unlike the shear-induced down-regulation, independent of active protein synthesis. Physiological shear stress (20 dynes/cm2) did not significantly activate PKC, as assessed by PKC translocation and enzymatic activity assay and failed to increase intracellular cAMP content. Furthermore treatment with calphostin C (1 microM) did not prevent the shear-induced down-regulation of ET-1. DNA transfection experiments suggest that the shear stress-responsive element of the ET-1 gene is contained in the sequence between -2.5 kb and -2.9 kb of the 5'-upstream region. Neither the transcription factor AP-1 binding site nor the GATA-2-factor binding site, necessary for the basal level of transcription of ET-1 gene, is sufficient to confer shear-responsiveness to the reporter gene. These results suggest that shear stress regulates the transcription of the ET-1 gene via an upstream cis element by a distinct mechanism not dependent on the PKC or cAMP pathways.Proceedings of the National Academy of Sciences 08/1993; 90(13):5999-6003. · 9.74 Impact Factor
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ABSTRACT: Hemodynamic shear stress alters the architecture and functions of vascular endothelial cells. We have previously shown that the synthesis of endothelin-1 (ET-1) in endothelial cells is increased by exposure to shear stress. Here we examined whether shear stress-induced alterations in cytoskeletal structures are responsible for increases in ET-1 synthesis in cultured porcine aortic endothelial cells. Exposure of endothelial cells to 5 dyn/cm2 of low shear stress rapidly increased monomeric G-actin contents within 5 min without changing total actin contents. The ratio of G- to total actin, 54 +/- 0.8% in quiescent endothelial cells, increased to 87 +/- 4.2% at 6 h and then decreased. Following the disruption of filamentous (F)-actin into G-actin, ET-1 mRNA levels in endothelial cells also increased within 30 min and reached a peak at 6 h. The F-actin stabilizer, phalloidin, abolished shear stress-induced increases in ET-1 mRNA; however, it failed to inhibit increases in ET-1 mRNA secondary to other stimulants. This indicates that shear stress-induced increases in ET-1 mRNA levels may be mediated by the disruption of actin fibers. Furthermore, increases in ET-1 gene expression can be induced by actin-disrupting agents, cytochalasin B and D. Another cytoskeleton-disrupting agent, colchicine, which inhibits dimerization of tubulin, did not affect the basal level of ET-1 mRNA. However, colchicine completely inhibited shear stress- and cytochalasin B-induced increases in ET-1 mRNA levels. These results suggest that shear stress-induced ET-1 gene expression in endothelial cells is mediated by the disruption of actin cytoskeleton and this induction is dependent on the integrity of microtubules.Journal of Clinical Investigation 11/1993; 92(4):1706-12. · 12.81 Impact Factor
- Journal of Clinical Investigation 02/1987; 79(1):1-6. · 12.81 Impact Factor