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

Based on the findings presented in this study, we propose the hypothesis that calcium could be a mediator for the development of atherosclerosis. Figure 8 shows a schematic illustration of the hypothesis. The presence of risk factors such as hypertension, hyperlipidemia, and smoking may increase the influx of calcium into vascular ECs. We have shown that reactive oxygen species, which are considered to be a risk factor for the development of atherosclerosis, actually increase [Ca++]i in vascular ECs. Increased intracellular calcium may damage the function of ECs, resulting in platelet aggregation at the damaged site. Increased intracellular calcium may also increase uptake of macromolecules in plasma such as fibrinogen and LDL, eventually forming atherosclerotic plaque. We have also shown that the influx of calcium into vascular ECs is associated with LDL transport across vascular ECs. The pretreatment by nifedipine inhibited both the increase in [Ca++]i and the increase in LDL transport, suggesting that intracellular calcium modulates LDL transport across ECs. Growth factors released from platelets may provoke migration and proliferation of medial SMCs in the aterial intima. It has been reported that migration of SMCs from arterial media to intima is enhanced by the presence of calcium, and can be inhibited by the pretreatment of calcium antagonist. As demonstrated in this study, calcium also plays an important role in the proliferation of SMCs provoked by some kinds of growth factors such as EGF. On the other hand, we found that an increased amount of dietary Mg suppressed the development of atherosclerotic lesions in the aorta of cholesterol-fed rabbits without affecting plasma total cholesterol and HDL-cholesterol concentrations. The mechanism of action might also be related to the calcium entry blocking action. The clinical and nutritional implications of these phenomena should be investigated further. The evidences presented in this study, however, would not be sufficient to fully explain the etiological role of calcium in atherogenesis. Further studies are required to elucidate the mechanism of the contribution of calcium to atherogenesis. The efficacy of calcium antagonist for the prevention of atherosclerosis in humans should also be investigated further.
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PMID:The role of calcium and magnesium in the development of atherosclerosis. Experimental and clinical evidence. 224 57

Emphasis is placed on the heterogeneity of the phenotypic presentation of PCOD. It is the common expression of an unknown number of disorders and thus is a sign and not a specific diagnosis. Two essential features are arrested follicular maturation and atresia of follicles. Normal folliculogenesis is described, emphasizing that a large number of areas could be subject to derangement causing PCOD. Any interference of the finely balanced sequence of events can lead to PCOD. The genetic defect causing familial PCOD is unknown and the initiating event remains undefined. Three families are described that illustrate four features of familial PCOD. A number of associated disorders such as diabetes, hyperinsulinemia, obesity, and hypertension are described. The potential importance of agents that modulate the LH and FSH activity that may cause PCOD is emphasized. The theoretic means by which similar male and female gonadal abnormalities may be coupled in families through growth factors EGF and alpha TGF are presented.
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PMID:Familial polycystic ovarian disease. 305 73

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

Autosomal dominant polycystic kidney disease (ADPKD) progresses to end-stage renal insufficiency before the age of 73 in approximately 48% of affected individuals. Why the disease, characterized by innumerable cysts arising in proximal and distal tubules, eliminates functioning non-cystic parenchyma in some patients and spares other is a mystery. The cysts initiate in early childhood in fewer than 1% of renal tubules as a consequence of the focal expression of mutated DNA. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of extracellular matrix proteins. Most of the cysts separate from the parent tubules and fill with fluid by cAMP-mediated chloride secretion. Risk factors associated with accelerated loss of renal function include: genotype (PKD Type 1 progresses more rapidly than PKD Type 2); gender (males progress more rapidly than females); race (black patients progress more rapidly than whites); hypertension; proteinuria. The relation between kidney size and progression to renal failure is debated. Progressive PKD is associated with the cellular expression of proto-oncogenes (fos, myc, ras, erb), growth factors (EGF, HGF, acid and basic FGF), chemokines (MCP-1. osteopontin), metalloproteinases, and apoptotic markers, and the interstitial accumulation of Types I and IV collagen, laminin, fibronectin, macrophages and fibroblasts, the magnitudes of which increase with age. Cyst activating factor (CAF), a neutral lipid identified in cyst fluid that stimulates fluid secretion and proliferation of renal epithelial cells and monocyte chemotaxis, has recently been identified as a potential progression factor. In those patients destined to develop renal failure there is loss of non-cystic parenchyma in association with mass replacement by fluid-filled cysts in a network of interstitial fibrosis. The decline in renal function is probably the consequence of processes leading to interstitial fibrosis, as in other nephropathies, rather than due to simple mechanical displacement of parenchyma by cysts.
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PMID:Mechanisms of progression in autosomal dominant polycystic kidney disease. 940 32

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 association of atherosclerosis with the most common risk factors including elevation of low density lipoprotein (LDL) levels, diabetes, hypertension and cigarette smoking, led to the hypothesis of "response to injury" to explain how the lesions develop. According to this hypothesis, one of the earliest events in atherogenesis is the accumulation of LDL in the arterial wall where they undergo oxidation. These LDL impair endothelial function, and thus, all the antiatherogenic properties of the endothelium. In addition, macrophages and smooth muscle cells take up these LDL, through different receptors, and become foam cells. The accumulation of foam cells in the arterial wall contributes to lesion development. Therefore, lesion development involves the activation of endothelial cells, as well as smooth muscle cells and monocytes/macrophages. In this activation different growth factors (PDGF, EGF, etc.), cytokines (IL-1b, TNFa, etc.) and the modified LDL themselves, play an important role. Through several signal transduction pathways these molecules activate transcription factors, such as the nuclear factor kappa B (NF-kB) or protooncogenes such as c-fos, c-myc, that regulate the expression of genes involved in the inflammatory/proliferative response of the lesions.
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PMID:[Cellular and molecular biology of atherosclerotic lesions]. 1118 11

The present studies test the hypothesis that contraction to EGF is dependent on mineralocorticoids and/or an elevation in systolic blood pressure (SBP). Endothelium-denuded thoracic aortas from sham normotensive, N(omega)-nitro-L-arginine (L-NNA) hypertensive, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR) were used in isolated tissue-bath experiments. Maximal contraction to epidermal growth factor [EGF; percentage of phenylephrine (PE; 10 umol/l)-induced contraction] was greater in strips from L-NNA (32 +/- 5%) and SHR (53 +/- 8%) rats compared with sham and WKY rats (17 +/- 1 and 12 +/- 4%, respectively). Wistar-Furth rats became only mildly hypertensive when given DOCA salt (134 +/- 6 mmHg) compared with Wistar rats (176 +/- 9 mmHg), but aortas from both strains had a similarly enhanced contraction to EGF (approximately 9 times the maximal contraction of sham aorta). Furthermore, in vitro incubation of aortas from Wistar and Wistar-Furth rats with aldosterone (10 nmol/l) increased EGF-receptor mRNA expression by >50%. These data indicate that arterial contraction to EGF may occur independent of hypertension and be stimulated by mineralocorticoids.
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PMID:Mineralocorticoids upregulate arterial contraction to epidermal growth factor. 1150 4

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

Angiotensin (Ang) II promotes the phosphorylation of extracellular regulated kinase (ERK); however, the mechanisms leading to Ang II-induced ERK phosphorylation are debated. The currently accepted theory involves transactivation of epidermal growth factor receptor (EGFR). We have shown that generation of phosphatidic acid (PA) is required for the recruitment of Raf to membranes and the activation of ERK by multiple agonists, including Ang II. In the present report, we confirm that phospholipase D-dependent generation of PA is required for Ang II-mediated phosphorylation of ERK in Wistar-Kyoto and spontaneously hypertensive rat preglomerular smooth muscle cells (PGSMCs). However, EGF stimulation does not activate phospholipase D or generate PA. These observations indicate that EGF recruits Raf to membranes via a mechanism that does not involve PA, and thus, Ang II-mediated phosphorylation of ERK is partially independent of EGFR-mediated signaling cascades. We hypothesized that phosphoinositide-3-kinase (PI3K) can also act to recruit Raf to membranes; therefore, inhibition of PI3K should inhibit EGF signaling to ERK. Wortmannin, a PI3K inhibitor, inhibited EGF-mediated phosphorylation of ERK (IC50, approximately 14 nmol/L). To examine the role of the EGFR in Ang II-mediated phosphorylation of ERK we utilized 100 nmol/L wortmannin to inhibit EGFR signaling to ERK and T19N RhoA to block Ang II-mediated ERK phosphorylation. Wortmannin treatment inhibited EGF-mediated but not Ang II-mediated phosphorylation of ERK. Furthermore, T19N RhoA inhibited Ang II-mediated ERK phosphorylation, whereas T19N RhoA had significantly less effect on EGF-mediated ERK phosphorylation. We conclude that transactivation of the EGFR is not primarily responsible for Ang II-mediated activation of ERK in PGSMCs.
Hypertension 2003 Mar
PMID:Role of EGFR transactivation in angiotensin II signaling to extracellular regulated kinase in preglomerular smooth muscle cells. 1262 96

Angiotensin II (AngII) plays a critical role in control of cardiovascular and renal homeostasis. In addition to its physiological action as a vasoconstrictor, growing evidence supports the notion that AngII contributes to cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The physiological and pathological actions of AngII in adults are mediated largely via the AngII type 1 receptor (AT1R), a heterotrimeric G-protein-coupled receptor (GPCR). Besides coupling with heterotrimeric G proteins to activate phospholipase C-beta (PLC-beta), AT1R also activates receptor tyrosine kinases (PDGF-R, EGF-R and IGF-R) and non-receptor tyrosine kinases (Src, Fyn, Yes, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK) and JAK2). These tyrosine kinases play critical roles in AngII-stimulated cell signal events.
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PMID:Angiotensin II signaling pathways mediated by tyrosine kinases. 1267 64


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