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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta-1 is the prototypical member of a class of growth factors whose actions have been strongly implicated in a number of pathophysiologic processes including chronic vascular diseases such as atherosclerosis and hypertension. One of the hall-marks of this class of growth factors is the diverse nature of their actions; a characteristic that is thought to arise from the fact that the effects of these factors are very dependent upon the particular cellular context in which they operate. There has been substantial progress in understanding the molecular signaling mechanisms utilized by these factors. These findings are beginning to provide a mechanistic framework with which to understand the complex and pleiotropic actions of these factors on cells and tissues of the cardiovascular system.
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PMID:TGF-beta in the cardiovascular system: molecular mechanisms of a context-specific growth factor. 1142

Parathyroid hormone-related peptide (PTHrP) is expressed throughout the cardiovascular system including coronary endothelial cells. Factors involved in the regulation of cardiac PTHrP expression have not been examined before. This study investigates the influence of transforming growth factor (TGF)-beta(1)on ventricular PTHrP expression. Coronary endothelial cells were isolated from ventricles of adult rats and PTHrP protein expression in these cultures was analysed by immunoblotting. TGF-beta(1)caused a concentration-dependent reduction in PTHrP protein within 24 h. In transgenic mice over-expressing TGF-beta(1)ventricular PTHrP protein expression and release was reduced compared to non-transgenic littermates. Similar concerns hold for PTHrP mRNA content (RT-PCR). Since ventricular TGF-beta(1)expression increases under pathophysiological conditions like arterial hypertension, ventricular PTHrP expression was further determined in aging spontaneously hypertensive (SHR-SP) and normotensive rats. TGF- beta(1)expression was increased in SHR-SP and ventricular PTHrP mRNA expression was downregulated at the age of 10 months. PTHrP expression did not recover in elder SHR-SP in which TGF-beta(1)expression was normalized again. Finally, we investigated ventricular PTHrP expression in rats after banding of the ascending aorta which generates a pressure induced hypertrophy without an induction of TGF-beta(1)expression. In ventricles from these animals, PTHrP expression was transiently increased and normalized at day 3. In conclusion, PTHrP expression was reduced under all conditions in which coronary endothelial cells were exposed to TGF-beta(1). PTHrP expression does not correlate with cardiac hypertrophy. Since coronary endothelial cells represent the majority of PTHrP producing cells in the ventricle its downregulation by TGF- beta(1)seems to be relevant for the paracrine effects of PTHrP.
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PMID:TGF-beta(1) downregulates PTHrP in coronary endothelial cells. 1144 22

Angiotensin (Ang) II, the main peptide of the renin angiotensin system (RAS), is a renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. This vasoactive peptide activates mesangial and tubular cells and interstitial fibroblasts, increasing the expression and synthesis of extracellular matrix proteins. Some of these effects seem to be mediated by the release of other growth factors, such as TGF-beta. In experimental models of kidney damage, renal RAS activation, cell proliferation, and upregulation of growth factors and matrix production were described. In some of these models, blockade of Ang II actions by ACE inhibitors and angiotensin type 1 (AT(1)) antagonists prevents proteinuria, gene expression upregulation, and fibrosis, as well as inflammatory cell infiltration. Interestingly, Ang II could also be involved in the fibrotic process because of its behavior as a proinflammatory cytokine, participating in various steps of the inflammatory response: Ang II (1) activates mononuclear cells and (2) increases proinflammatory mediators (cytokines, chemokines, adhesion molecules, nuclear factor kappaB). Finally, Ang II also regulates matrix degradation. These data show that drugs controlling this complex vasoactive peptide are probably one of the best ways of avoiding fibrosis in progressive renal diseases.
Hypertension 2001 Sep
PMID:Angiotensin II and renal fibrosis. 1156 46

One of the striking morphological features of renal failure is an increase of cell volume. This review explores the role of cell volume regulatory mechanisms in the pathophysiology of progressive renal disease. The case is made that TGF-beta, a major cytokine involved in the development of progressive renal failure, upregulates the transcription of the serum and glucocorticoid-dependent kinase hSGK1, involved in cell volume regulation. Excessive extracellular glucose concentrations stimulate TGF-beta1 expression and thus similarly enhance hSGK1-transcription. The kinase stimulates two mechanisms important for cell volume regulation, i.e. the renal epithelial Na+ channel ENaC and the thick ascending limb Na+,K+,2Cl- cotransporter BSC1. On the one hand, stimulation of renal tubular transport leads to renal retention of Na+, which favours the development of hypertension. On the other, the increase of cell volume stimulates protein synthesis and inhibits protein degradation, contributing to the enhanced net formation and deposition of matrix proteins. At later stages, the increase of cell volume may be reversed to atrophy, and cell death may lead to loss of functional tissue. In conclusion, progressive renal disease is paralleled by deranged cell volume regulatory mechanisms.
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PMID:Cell volume regulatory mechanisms in progression of renal disease. 1173 Feb 63

Cyclosporine nephropathy (CyAN) is a major limiting factor in the otherwise successful widespread use of cyclosporine in solid organ transplant. Transforming growth factor-beta1 (TGF-beta1) has been implicated as an important fibrogenic cytokine in the development of this disease. TGF-beta-inducible gene-H3 (beta(ig)-H3) is a TGF-beta1- induced gene product, which acts as a marker for biologically active TGF-beta1. This study reports TGF-beta1 gene expression and beta(ig)-H3 tissue distribution in non-renal allograft CyAN. Renal tissue from nine patients who had developed CyAN after successful heart or heart-lung transplantation and from four kidneys removed for tumour were analyzed for TGF-beta1 gene expression beta(ig)-H3 protein with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. TGF-beta1 gene expression was increased in CyAN compared to nephrectomy (P<0.0001). Beta(ig)-H3 protein expression was identified in distal convoluted tubular epithelium and parietal glomerular epithelium in CyAN, and not in nephrectomy samples. Expression of TGF-beta1 mRNA was significantly higher in renal tissue from patients not receiving angiotensin converting enzyme inhibitor (ACEI) therapy for hypertension (P<0.05). These findings support the hypothesis that TGF-beta1 is an important cytokine in the development of CyAN, independent of its role in chronic rejection in renal allografts.
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PMID:Transforming growth factor-beta1 and tumor growth factor-beta-inducible gene-H3 in nonrenal transplant cyclosporine nephropathy. 1174 Mar 78

Proteinuria is the hallmark of renal disease and proteinuria exceeding 1 gm a day in patients with renal disease augers a poorer prognosis. Proteinuria has been shown to be tubulotoxic and directly contributes to renal deterioration. Patients with non-selective proteinuria are more likely to have progressive renal disease. Diabetic patients with persistent microhaematuria have about 20 times the risk of developing diabetic nephropathy. In essential hypertension, the onset of de novo proteinuria after years of adequate BP control is a marker of subsequent decline in renal function. In glomerulonephritis, more severe proteinuria is associated with faster rate of progression. Even though the initial phase of proteinuria in patients with glomerulonephritis is usually of immunological origin, in the vast majority of patients with established disease, the latter progressive phase of proteinuric glomerulopathy is the result of glomerular hyperfiltration which shifts glomerular non-selective pores to larger dimensions resulting in excessive leakage of protein in the urine. Endothelial injury resulting from glomerular hyperfiltration causes increase in local generation of Angiotensin II in the kidney as part of the hemodynamic response. ACE inhibitors and angiotensin II receptor antagonists (ATRA) can improve glomerular pore-selectivity by remodelling the glomerular basement membrane. In addition, these agents also have beneficial effects by decreasing TGF-beta production therapy decreasing mesangial cell proliferation, hence ameliorating disease progression in patients with diabetic nephropathy and IgA nephropathy. A number of recent clinical trials have shown that ACEI and ATRA therapy can retard the progression of renal deterioration in patients with NIDDM and those with IgA nephropathy and even restore normal renal function in those with mild renal impairment. Treatment and control of proteinuria in patients with renal disease should be regarded as important as treatment of hypertension as it can prevent renal failure.
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PMID:Proteinuria: clinical signficance and basis for therapy. 1176 58

The aim of the present study was to elucidate how transforming growth factor-beta(1) (TGF-beta(1)) can stimulate collagen deposition in cardiac tissue by interstitial cells via stimulation of fibroblasts, via myofibroblasts, or via differentiation of fibroblasts to myofibroblasts. The dose- and time-dependent stimulation of collagen production and of expression of alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts, was studied in cultures of second-passage adult rat cardiac fibroblasts. The TGF-beta(1)-stimulated collagen production is positively correlated (r=0.68, P<0.001) with the appearance of alpha-SMA. Only at high concentrations (40 to 600 pmol/L) and after a long time (24 to 48 hours) of incubation, TGF-beta(1) increases the collagen production and stimulates the differentiation of fibroblasts to myofibroblasts. The maximal stimulation of the collagen production (2-fold, P<0.001) observed after incubation of cultures of fibroblasts with 600 pmol/L TGF-beta(1) for 48 hours is accompanied by a maximal stimulation of alpha-SMA expression (3.5-fold, P<0.001), when cultures consist mainly of myofibroblasts. The stimulation of collagen production cannot be reversed either after additional incubation of TGF-beta(1)-stimulated second-passage cultures for 2 days or in their offspring in the next third passage after incubation for 7 days without TGF-beta(1). The increased collagen production in these third-passage cultures cannot be further stimulated by TGF-beta(1). Our data suggest that TGF-beta(1)-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of the collagen production either in fibroblasts or in myofibroblasts. Instead, TGF-beta(1) induces the differentiation of fibroblasts to myofibroblasts, which have a higher activity for collagen production than fibroblasts.
Hypertension 2002 Feb
PMID:Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. 1184 94

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

Cardiac hypertrophy refers to the abnormal growth of cardiomyocytes, and is often caused by valvular heart disease and hypertension. It involves the activation of growth, including increased protein synthesis and changes in gene expression. Transforming growth factor-beta1 (TGF-beta1) may play a central role in protecting the heart during the hypertrophic response by helping to restore normal functions of the affected myocardium. We tested the hypothesis that cardiomyocytes respond to stretch-induced paracrine hypertrophic stimuli with increased expression of TGF-beta1. To that purpose, we investigated whether angiotensin II (All), endothelin- I (ET-1) and TGF-beta, secreted by stretched cardiac and vascular cells, are involved in the paracrine mechanisms of stretch-induced changes of TGF-beta1 mRNA expression in stationary (i.e. non-stretched) cardiomyocytes. Our results indicated that TGF-beta1 mRNA expression in stationary cardiomyocytes was increased by AII release from cardiomyocytes that had been stretched for 30-60 min. Furthermore, it is likely that ET-1 and TGF-beta were released by stretched cardiac fibroblasts and endothelial cells to induce TGF-beta1 mRNA expression in stationary cardiomyocytes. Stretched vascular smooth muscle cells did not influence TGF-beta1 mRNA expression in stationary cardiomyocytes. These results indicate that AII, ET-I and TGF-beta, released by cardiac cell types, act as paracrine mediators of TGF-beta1 mRNA expression in cardiomyocytes. Therefore, we conclude that in stretched myocardium the cardiomyocytes, cardiac fibroblasts and endothelial cells take part in intercellular interactions contributing to cardiomyocyte hypertrophy.
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PMID:Stretch-induced paracrine hypertrophic stimuli increase TGF-beta1 expression in cardiomyocytes. 1219 Jan 14

Cyclosporin is a powerful stimulator of oxidative stress signaling, leading to TGFbeta production, NO degradation, endothelial dysfunction, hypertension and post-transplant nephropathy. Carvedilol, alpha1-beta-blocker with strong antioxidant activity, may interfere with this chain of events. Therefore, we measured monocyte ecNOS, TGFbeta and heme oxygenase-1 (HO-1) mRNA level and plasma nitrite/nitrate, 3-nitrotyrosine, an estimate of peroxynitrite, and total plasma antioxidant power in kidney-transplanted patients with post-transplant hypertension, before and after treatment with carvedilol, 25 - 50 mg o.d. orally for 4 months (n = 15). The dihydropyridine calcium channel blocker nifedipine (n = 10) was used as comparator antihypertensive drug. Blood pressure fell to a similar extent with both drugs. Carvedilol increased plasma antioxidant power and HO-1 mRNA and reduced 3-nitrotyrosine and TGFbeta mRNA levels, while the same was not observed with nifedipine. Monocyte ec NOS mRNA levels and plasma nitrite/nitrate were higher in the patients than in a normotensive healthy control group and were unaffected by either treatment. In conclusion, carvedilol reduces the oxidative stress and corrects the altered cellular signaling mediated by oxidative stress in CsA-induced post-transplant hypertension. Therefore, it may prevent long-term complications, such as endothelial dysfunction, fibrogenesis and post-transplant nephropathy by decreasing NO degradation and production of TGFbeta, a key fibrogenic cytokine, and by activating HO-1 production.
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PMID:Oxidative stress and TGFbeta in kidney-transplanted patients with cyclosporin-induced hypertension. Effect of carvedilol and nifedipine. 1222 81


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