Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the importance of Ca2+ influx via voltage-dependent Ca2+ channels in the mechanism of vascular remodeling, we investigated effects of a new Ca2+ channel blocker manidipine on DNA and protein syntheses stimulated by several mitogens in cultured rat vascular smooth muscle cells (VSMC) and bovine endothelial cells (EC), and growth-related immediate early proto-oncogenes expression in VSMC. Endothelin-1 (ET-1) induced receptor-mediated phosphoinositide breakdown and increased cytosolic free Ca2+ levels in rat VSMC, with concomitant increases in proto-oncogenes (c-fos c-myc) mRNA levels as well as DNA and protein syntheses. Manidipine dose-dependently (10(-9) M to 10(-6) M) inhibited DNA, and protein syntheses stimulated by 10(-7) M ET-1 in rat VSMC; manidipine was a more potent inhibitor for protein synthesis (IC50: 10(-8) M) than for DNA synthesis (IC50: 10(-7) M). Manidipine also inhibited DNA synthesis stimulated by 10 ng/mL bFGF and 2.5% FCS in rat VSMC and bovine EC; manidipine was more potent in inhibiting DNA synthesis stimulated by bFGF than that by FCS in both cells. The expression of ET-1-induced c-fos and c-myc mRNAs levels was unaffected by manidipine. These results suggest that manidipine has potent inhibitory effects on the ET-1-induced hyperplasia and/or hypertrophy of VSMC, as well as on the bFGF-induced hyperplasias of VSMC and EC, thus implicating its potential usefulness for preventing abnormal VSMC proliferation and angiogenesis associated with hypertension and atherosclerosis.
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PMID:Effects of manidipine on DNA and protein syntheses in cultured vascular smooth muscle and endothelial cells and on proto-oncogene expression. 134 86

Endothelins are produced by endothelial and epithelial cells, macrophages, fibroblasts, and many other types of cells. Their receptors are present in numerous cells, including smooth muscle cells, myocytes, and fibroblasts. Evidence now suggests that the three isoforms of endothelins (ET-1 and the other two related isopeptides, ET-2 and ET-3) regulate growth in several of these cells. Endothelin-1 influences DNA synthesis, the expression of protooncogenes, cell proliferation, and hypertrophy. The participation of ET in mitogenesis involves activation of multiple transduction pathways, such as the production of second messengers, the release of intracellular pools of calcium, and influx of extracellular calcium. Moreover, ET-1 acts in synergism with various factors, such as EGF, PDGF, bFGF, TGFs, insulin, etc., to potentiate cellular transformation or replication. Several of these factors may in turn stimulate the synthesis and/or the release of endothelins. The production and release of endothelins are also increased in acute and chronic pathological processes, e.g., atherosclerosis, postangioplastic restenosis, hypertension, and carcinogenesis. It is postulated that endothelins act in a paracrine/autocrine manner in growth regulation and play an important role mediating vascular remodeling in some cardiovascular diseases. The present review analyses the implication of endothelins (ET-1, -2, and -3) in physiopathology related to their growth regulatory properties.
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PMID:Growth regulatory properties of endothelins. 848 16

Aortic fibronectin (FN) expression is augmented in hypertension. Increasing evidence suggests that both angiotensin II (Ang II) and mechanical factors may induce vascular remodeling in response to hypertension. We have previously shown that, in vitro, increased transmural pressure enhances FN expression in rabbit aortic media. To investigate the existence of a link between the effects of pressure and Ang II and to explore the mechanisms underlying such a relationship, we quantified the effect of Ang II and Ang II inhibitors on the pressure-dependent FN expression in a 3-day organ culture model of rabbit aorta using immunolabeling analysis and detected FN mRNAs by in situ hybridization. A dose-dependent effect of Ang II on FN expression was observed at both 80 and 150 mm Hg but not at 0 mm Hg (relaxed vessels). One mumol/L Ang II increased the media cross-sectional surface, showing FN expression from 7.9 +/- 0.7% (n = 9) to 18.9 +/- 1.1% (n = 4) at 80 mm Hg (P < .01) and from 17.4 +/- 1.8% (n = 9) to 56.6% +/- 3.6 (n = 4) at 150 mm Hg (P < .001). In situ hybridization revealed that Ang II and pressure upregulated FN mRNA expression. Losartan, an AT1 antagonist, not only blocked the Ang II effect but also inhibited the transmural pressure effect. Angiotensin-converting enzyme inhibition abolished the pressure-dependent FN expression and significantly diminished the effect of pressure in the presence of Ang II. The effect of renin-angiotensin system inhibitors was specific for FN, since neither bFGF nor laminin expression was affected by these agents. Taken together, the results demonstrate that (1) the effect of transmural pressure is mediated by the stimulation of a local renin-angiotensin system, resulting in a net Ang II production in the culture medium, (2) transmural pressure and Ang II act synergistically to enhance vascular FN expression, (3) AT1 receptors mediate both the effects of pressure and of exogenous Ang II, and (4) the effect of Ang II on FN expression is regulated at a pretranslational level.
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PMID:Pressure and angiotensin II synergistically induce aortic fibronectin expression in organ culture model of rabbit aorta. Evidence for a pressure-induced tissue renin-angiotensin system. 892 71

Long-term use of hydrochlorothiazide (HCTZ), a common diuretic agent for hypertension, has been associated with increased bone density and reduced hip fracture rates in patients. In this study, we sought to examine whether HCTZ has an anabolic effect on the proliferation of human osteoblasts (derived from either vertebrate or rib bone samples) in vitro. Cell proliferation was determined by [3H]thymidine incorporation and cell number counting. In medium supplemented with 1% bovine calf serum, HCTZ significantly and reproducibly increased [3H]thymidine incorporation and cell number. The stimulatory effect was dose dependent in a biphasic manner, with the maximal stimulation (approximately 60% above control, P < 0.001) seen at 1 microM HCTZ. In fresh serum-free medium, HCTZ was ineffective as a bone cell mitogen, indicating that the bone cell mitogenic activity of HCTZ required a serum growth factor (GF). HCTZ at doses greater than 10 microM was inhibitory in the presence or the absence of serum, presumably because of the cytotoxic effects. The serum requirement for the bone cell mitogenic activity of HCTZ could be replaced with a conditioned medium (conditioned with normal human osteoblasts for 24 hours), or with a mitogenic dose (1 ng/ml) of PDGF. The GF requirement was specific for PDGF, because other bone cell-derived growth factors (i.e., TGFbeta, IGF-I, IGF-II, and bFGF) were unable to replace serum for the bone cell mitogenic activity of HCTZ. In summary, this study shows that (1) HCTZ stimulated the proliferation of normal, untransformed, human osteoblasts in vitro; (2) the bone cell mitogenic effect of HCTZ required the presence of a serum GF; (3) the serum requirement could be replaced with a bone cell GF in conditioned medium; (4) the GF requirement was specific for PDGF. In conclusion, we have demonstrated for the first time that HCTZ has a direct anabolic effect on human osteoblasts in vitro, and that the mitogenic activity is dependent on the presence of PDGF. Because increased bone cell proliferation is a key determinant of bone formation, these observations raise the interesting possibility that HCTZ could act directly on bone cells to stimulate bone formation in patients.
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PMID:Mitogenic action of hydrochlorothiazide on human osteoblasts in vitro: requirement for platelet-derived growth factor. 893 80

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

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.
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PMID:Changes of plasma endothelin and growth factor levels, and of left ventricular mass, after chronic AT1-receptor blockade in human hypertension. 963 90

Chronic rejection is the most common cause of the long term renal graft loss. It is characterized by luminal thickening and obliteration, interstitial sclerosis, glomerulosclerosis and tubular atrophy development. The pathology is still unclear. Alloantigen-dependent factors (acute rejection, HLA mismatch) and allograft-independent factors (ischaemia-reperfusion, hyperlipidaemia, hypertension, infection, nephrotoxicity, reduced nephron dose) have been implicated in the etiology of chronic rejection. As a result of these factors, endothelial cells are activated and express a variety of adhesion molecules, cytokines and growth factors. Lymphocytes and macrophages infiltrate the areas of local damage and express other cytokines and growth factors (TGF, bFGF, PDGF). In the next step, vascular smooth muscle cells proliferate and migrate from the media into the vascular intima and produce local extracellular matrix. Which factors are the most important and which mechanisms are the key for the development of chronic rejection are in the focus of ongoing research.
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PMID:[Chronic rejection of renal allografts. Part 1. Present knowledge of etiopathogenesis]. 1074 33

The authors present the results of experimental and clinical trials of recombinant genes coding the synthesis of endothelial growth factors VEGF, bFGF. Single transendocardial administration of these genes' DNA into the zone of hybernating myocardium in some patients with CHD caused in 3-6 months significant increase in perfusion, left ventricular ejection fraction, decrease in stenocardic pang rate, increase in exercise tolerance. The marked clinical effect was achieved when these drugs were introduced into ischemized tissue in patients with obliterating atherosclerosis of lower extremity arteries. Development of the methods for studying endothelial function available for wide clinical practice will permit to raise the efficiency of initial and secondary prophylaxis of arterial hypertension, CHD. Today the evaluation and correction of endothelial dysfunction is the new and the most perspective direction in cardiology development.
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PMID:[Endothelial dysfunction and its clinical significance (new trend in cardiology)]. 1155 Mar 27

Hypertrophy of vascular smooth muscle cells occurs during hypertension-induced remodelling of arteries and during development of arteriosclerosis and restenosis following angioplasty but the pathogenesis of the hypertrophic status is not yet fully understood. In a previous study we demonstrated that the synthetic non-sulfated, non-toxic heparin-mimicking compound RG-13577 is capable of inducing a cell cycle-arrested hypertrophic phenotype of coronary smooth muscle cells. In this study we clarify the mode of action of RG-13577 and demonstrate that the RG-13577-induced hypertrophy is associated with an increased expression of TGF-beta1 as indicated by an increase in TGF-beta1-specific protein and mRNA level. Furthermore we show that RG-13577-treated hypertrophic smooth muscle cells maintain full metabolic activity as indicated by a continuous de novo synthesis of protein and proteoglycans and that the RG-13577-induced growth arrest is caused not only by a higher expression of TGF-beta, but also by a reduced response of RG-treated cells to the mitogenic activity of bFGF, PDGF and EGF. The growth inhibitory activity of RG-13577 is reduced in the presence of neutralizing antibodies against TGF-beta. TGF-beta itself has anti-proliferative activity in serum-depleted medium. The RG-13577 effect is reversible since incubation of hypertrophic cells in RG-13577-free medium restores cell volume and [3H]thymidine incorporation to the values of untreated control cells within 4 days. We conclude, that the active metabolic status of RG-13577-treated cells in association with the overexpression of TGF-beta could promote repair processes of injured arteries after angioplasty without stimulating cell proliferation.
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PMID:Induction of a hypertrophic growth status of coronary smooth muscle cells is associated with an overexpression of TGF-beta. 1199 65

Migration of adventitial fibroblasts (AF) is involved in the neointimal formation which is one of the common pathological processes in several vascular diseases. The observation of whether the migratory response of AF from hypertensive animal is different from that of controls may provide an explanation of vascular remodeling in hypertension. We examined whether there is any difference between the migratory activity of AF derived from spontaneously hypertensive rat (SHR) and that from their normotensive counterpart Wistar-Kyoto rats (WKY). In addition, the role of osteopontin (OPN) in cell migration was also examined. Primary cultures of aortic adventitial fibroblasts were derived from SHR and age-matched WKY. Migration of fibroblasts was determined with the Transwell method. The mRNA expression level of OPN was measured by a real-time quantitative PCR. When compared with WKY-derived cells, migration of adventitial fibroblasts from SHR exhibited an increased response when stimulated by 10% serum (cell number per field 35.20+/-5.26 vs 22.2+/-3.27, p<0.05). Chemotaxis induced by 10 ng/ml bFGF showed a similar difference (cell number per field 30.23+/-4.54 vs 19.20+/-4.47, p<0.05). We also found that SHR-derived fibroblasts expressed a higher level of OPN mRNA than the cells from WKY (1863.23+/-43.91 vs 326.24+/-68.29, p<0.01). To verify if OPN is associated with the enhanced migratory ability in AF from SHR, we designed the antisense oligonucleotide of OPN. The results showed that the antisense OPN oligonucleotide significantly inhibited AF migration (cell number per field 38.60+/-5.98 vs 26.61+/-3.84, p<0.05), while sense and mismatch OPN oligonucleotide had no effect on cell migration. Therefore, the migration of adventitial fibroblasts appeared to be enhanced in cultures derived from SHR. OPN might be involved in the difference observed.
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PMID:[Osteopontin enhances migratory ability of cultured aortic adventitial fibroblasts from spontaneously hypertensive rats]. 1498 24


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