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)

High potassium diets greatly reduce intimal and medial thickening in stroke-prone spontaneously hypertensive rats (SHRSP). In vascular smooth muscle cells, transforming growth factor-beta (TGF-beta) inhibits proliferation. To test whether high potassium diets decrease aortic thickening through TGF-beta, we measured TGF-beta-like activity in medium bathing aortas from rats fed either normal potassium or high potassium diets. Five-week-old SHRSP were fed 6% high NaCl diets containing either normal (0.5%) potassium (11 rats) or high (2.1%) potassium (14 rats) for 7 weeks. Aortas were freshly excised and perfused for 3 hours with tissue culture medium at ordinary arterial pressures. TGF-beta-like activity in the acid-activated perfusing medium was assessed using the growth inhibitory action on mink lung cells. Growth inhibition was assessed by [3H]thymidine incorporation. In the medium perfusing the outside of the aorta, the growth inhibitory rates were 2.5 times higher in high potassium SHRSP than in normal potassium SHRSP (-49% versus -20%, p less than 0.03). Antibodies to TGF-beta 1 and TGF-beta 2 were added to other aliquots and did not alter the results whatsoever. Thus, the difference in growth inhibition was not due to differences in TGF-beta. The high potassium aortas released 2.5 times more growth-inhibiting agents than the normal potassium aortas. The same pattern of growth inhibition was also seen using vascular smooth muscle cells rather than mink lung cells (r = +0.818, p less than 0.001, n = 13). The increased growth inhibition of high potassium aortas was not due to an increased release of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:High potassium diets greatly increase growth-inhibiting agents in aortas of hypertensive rats. 159 76

While the roles of the platelet-derived growth factors (PDGFs) in vascular smooth muscle cells (SMCs) continue to be elucidated, these cells, especially in their activated 'synthetic' state, have also been found to express, and proliferate in response to, many of the other families of polypeptide growth factors, such as the fibroblast growth factors. Other stimulators of DNA synthesis, and particularly of SMC hypertrophy, include the vasoconstrictor hormones such as angiotensin II, as well as physical forces, especially stretch or tension. For many of these ligands, multiple receptors have been identified and their means of signal transduction are being characterized rapidly. Regulatory regions of these genes are being identified as are transcription factors. Complex post-transcriptional regulation has also been shown by the findings that some growth factors are phosphorylated, or translocated to the nucleus or the extracellular matrix. Inhibitors have also been identified. These include some prostaglandins, calcium antagonists, agonists that activate guanylate and adenylate cyclases, inhibitors of angiotensin-converting enzyme, interferon gamma, and heparin. Future studies are likely to show that tyrosine phosphatases and recessive oncogenes also regulate growth. The existence of so many autocrine/paracrine mitogens--together with some experimental data--suggests some redundancy in the system as well as some additive effects. Redundancy may limit the efficacy of antibodies to a single growth factor to block cell proliferation. Their evolutionary conservation implies some unique roles for each growth factor but these have not been apparent from in vitro studies to date. Further insights are apt to come from the increasing recognition that growth factors have other effects--on cell attachment, migration, survival, production of extracellular matrix, thrombosis, vaso-constriction, regulation of cytokine synthesis, and inhibition of growth. Many of these effects may prove to be context-dependent, as with the case of growth inhibition by transforming growth factor-beta. Studies in monolayer cultures may not obtain the same results as studies using cocultures of endothelial and smooth muscle cells, or 3-dimensional matrix cultures, organ cultures, or in the intact animal. In vivo descriptive studies of growth factors expressed in vascular embryogenesis, hypertension, atherosclerosis, acute balloon injury and thrombosis are being supplemented by interventions such as infusions with growth factors, antibodies, and toxin conjugates. These studies, and studies using transgenic mice and homologous recombination, should yield information as to mechanisms and may also suggest new therapies.
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PMID:Smooth muscle cell growth factors. 181 90

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10(-7), 10(-6) M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10(-7), 10(-6) M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-beta (4 x 10(-11), 4 x 10(-10) M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.
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PMID:Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. 217 26

Hypertension causes biochemical and morphological changes in the vessel wall by unknown mechanisms. Locally produced substances may have a role in mediating these vascular changes. We have studied the expression of platelet-derived growth factor (PDGF) B chain and PDGF A chain, insulin-like growth factor (IGF)-I and IGF-II, endothelial cell growth factor (ECGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-beta) in aortic tissue from normotensive rats and rats made hypertensive by deoxycorticosterone (DOC)/salt treatment. Using Northern blotting, we found that genes for each of these growth factors were transcriptionally active in the aorta of both normotensive and hypertensive rats. TGF-beta aortic mRNA levels increased up to threefold as a result of DOC/salt hypertension. In contrast, no major changes in the expression of either PDGF chain, IGF-I or II, ECGF, or bFGF were detectable. The results indicate that at least seven genes coding for growth factors that were shown previously to influence growth and function of vascular cells in vitro, are expressed in rat aorta in vivo. These findings support the hypothesis that synthesis and release of growth factors in the arterial wall are involved in autocrine and/or paracrine regulatory mechanisms. In addition, the increased expression of TGF-beta in vivo may have a role in mediating the aortic changes induced by hypertension.
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PMID:Growth factor expression in aorta of normotensive and hypertensive rats. 270 37

Transforming growth factor-beta, a peptide growth factor, is known to be a multifunctional regulator of cellular activity. The effect of this growth factor on extracellular matrix formation is well established, but its effects on elastin, a critical component of lung, skin, and blood vessels are unknown. In the present study, by use of an Enzyme-Linked Immunoassay method, we found that transforming growth factor-beta strongly increased elastin production in cultured porcine aortic smooth muscle cells. In a dosage-dependent study, 1.0-10.0 ng/ml transforming growth factor-beta promoted elastin production 2-3 fold. In a time-dependent study, at least an 8 h pre-treatment with 10.0 ng/ml transforming growth factor-beta was required for sustained increases in elastin production. The effects of transforming growth factor-beta on cultured aortic smooth muscle cells suggest that this cytokine may be an important mediator of elastin formation during atherosclerosis and hypertension.
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PMID:The elastogenic effect of recombinant transforming growth factor-beta on porcine aortic smooth muscle cells. 316 37

Structural changes of the heart and blood vessels participate in the long-term regulation of the cardiovascular system. In hypertension and myocardial dysfunction, the adaptive process of cardiac and vascular remodeling may contribute to the pathophysiology and complications of these diseases. Recent investigations have enhanced our understanding of the cellular and molecular biology of vascular smooth muscle and cardiac myocyte growth. Mechanical and neurohormonal factors can independently stimulate hypertrophy-hyperplasia in vascular and cardiac myocytes. Increased pressure-stretch of cardiac myocyte and vascular smooth muscle cells can activate protooncogene expressions that may mediate the growth response. Vasoactive substances also regulate cardiovascular growth. In general, endogenous vasoconstrictors (eg, angiotensin, endothelin) act as growth promoters, and endogenous vasodilators (eg, nitric oxide, prostacyclin, atrial natriuretic peptide) act as growth inhibitors of vascular smooth muscle and, possibly, cardiac myocytes. Recent data have demonstrated that the vasoconstrictive agents, such as angiotensin, activate protooncogenes and autocrine growth factors that mediate vascular growth. Furthermore, the development of vascular hypertrophy versus hyperplasia is dependent on the relative activation of endogenous proliferative growth factor (eg, platelet-derived growth factor, basic fibroblast growth factor) versus antiproliferative factor (eg, transforming growth factor-beta) by the growth stimulus. Taken together, these data demonstrate that complex interactions of local mediators, which participate in the pathophysiology of cardiovascular diseases, control cardiovascular growth.
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PMID:The role of mechanical and humoral factors in growth regulation of vascular smooth muscle and cardiac myocytes. 792 63

The main target organ in untreated arterial hypertension (HTA) is the blood vessel wall (BVW) of the high pressure system (conductance and resistance arteries), which is primarily responsible for vital organ integrity. Three major structural changes develop in the BVW in experimental and human HTA: hypertrophy of the smooth muscle (increased thickness of the media), reduction in the amount of elastin and increased interstitial collagen deposition. The latter two structural changes are responsible for the increased stiffness (reduced compliance) that characterizes the BVW in untreated HTA. Angiotensin II, endothelins, nitric oxide, local growth factors (fibroblast-derived growth factor, platelet-derived growth factor, transforming growth factor-beta) and metalloproteinases are involved in BVW remodelling, and represent potential targets for drug action. Angiotensin-converting enzyme (ACE) inhibitors are particularly suited for such actions via their angiotensin II-, bradykinin- and/or interstitial metalloproteinases-dependent actions. Unfortunately, limited data are available on BVW protection with conventional ACE inhibitors. The new ACE inhibitor perindopril differs from most others in terms of BVW protection. In carefully designed morphometric experiments, perindopril has been shown to reduce vascular smooth muscle hypertrophy and to normalize the elastin:collagen ratio in the BVW of hypertensive rats. It has been shown that perindopril is unique in that respect since isradipine, metoprolol, hydralazine and captopril all failed to normalize the media:lumen ratio in the hypertensive rat. The functional counterpart of these in vitro structural findings obtained with perindopril has been demonstrated in human HTA patients; increased brachial artery diameter and compliance were observed after three weeks of perindopril.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The blood vessel as a target organ in hypertension: protective effect of perindopril. 795 36

Immunosuppressants such as cyclosporine are considered to constrain cell growth by preventing the production of growth stimulatory cytokines (e.g., interleukin-2). The possibility exists, however, that CsA and other immunosuppressants might restrain cell growth by promoting the production of growth-inhibitory cytokines. We have explored herein the hypothesis that CsA stimulates the production of transforming growth factor-beta (TGF-beta), and restrains new DNA synthesis in mammalian cells via a TGF-beta-dependent mechanism. To investigate this new postulate independently of an IL-2-dependent mechanism, we utilized, as probes, two mammalian cell lines, distinguished by their sensitivity to growth inhibition by TGF-beta and resistance to IL-2: CCL-64 mink lung epithelial cells (CCL-64 cells) and A-549 human adenocarcinoma cells (A-549 cells). Our experimental approach revealed the following: (A) CsA and not cyclosporine H, an inactive analogue of CsA, mediates growth inhibition of TGF-beta-sensitive cells, CCL-64 cells, and A-549 cells; (B) CsA stimulates these mammalian cells to secrete TGF-beta; and (C) TGF-beta induced by CsA is biologically active in inducing cell growth inhibition (demonstrated by the reversal of CsA-associated inhibition with anti-TGF-beta monoclonal antibodies). Our observations suggest that CsA can regulate cell growth via a TGF-beta-dependent mechanism. Since the multifunctional cytokine TGF-beta can enhance extracellular matrix accumulation as well as augment endothelin production, our findings also advance a mechanism that links, via TGF-beta, the beneficial (immunosuppression) and the harmful (fibrosis, hypertension) consequences of CsA usage.
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PMID:Regulation of new DNA synthesis in mammalian cells by cyclosporine. Demonstration of a transforming growth factor beta-dependent mechanism of inhibition of cell growth. 811 45

The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIalpha and cGKIbeta. The former is more sensitive to cGMP than the latter. In humans, cGKIbeta cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIalpha have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human CGKIalpha cDNA (-36 to +2177; the translation start site: +1) enclosing the 671-amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIbeta cDNA. Southern blot analysis suggested that human cGKIalpha and cGKIbeta are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIalpha mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIbeta mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4 x 10(-10) mol/L platelet-derived growth factor. Angiotensin II (10(-8) mol/L), transforming growth factor-beta (4 x 10(-11) mol/L), and tumor necrosis factor-alpha (6 x 10(-6) mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
Hypertension 1996 Mar
PMID:cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. 861 2

Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti-transforming growth factor-beta antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT1 receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1-mediated effects, whereas, the ETA receptor antagonist BQ-123 diminished the Ang II-induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETA and AT1 receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis.
Hypertension 1996 Apr
PMID:Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. 861 64


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