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)

Abnormal growth of vascular smooth muscle (VSM) is seen in various pathologic conditions such as hypertension and atherosclerosis. Many classic vasoconstrictors have now been shown to be mitogenic, either by themselves or in conjunction with other cofactors, such as insulin. The mitogenic effects of vasoconstrictors may be due, in part, to activation of similar second messenger pathways, including stimulation of the Na+/H+ antiporter. It has been suggested, therefore, that an enhanced proliferation rate may be, in part, the consequence of elevated Na+/H+ exchange. This hypothesis is supported by several observations of the close association between Na+/H+ exchange activity and DNA synthesis in some cell types including fibroblasts and VSM. Stimulation of Na+/H+ exchange may play a permissive role in optimal growth by preventing H+ accumulation (a fall in intracellular pH [pHi]) due to the increased metabolic activity during cell stimulation. Enhancement of Na+/H+ exchange activity increases Na+ influx into the cell, and secondarily increases K+ entry through activation of Na+/K+ ATPase activity. Although the Na+/H+ antiporter may influence cell proliferation through various ionic mechanisms, it is not clear that enhanced proliferation is the consequence of overactivity of this antiporter. In VSM, there are also differences in the pattern of activation of the Na+/H+ antiporter by hyperplastic and hypertrophic agents. Although pHi is increased in response to both acute and chronic stimulation by hyperplastic factors, such as platelet-derived growth factor, a hypertrophic agonist such as angiotensin II increases pHi acutely but lowers it chronically. Likewise, hyperplastic factors increase the Na+/H+ antiporter (NHE-1) mRNA levels, whereas angiotensin II does not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Na+/H+ exchange and vascular smooth muscle proliferation. 814 Nov 73

Cultured vascular smooth muscle cells derived from the spontaneously hypertensive rat (SHR) are known to replicate more rapidly than cells from the normotensive Wistar-Kyoto (WKY) rat. In this study we compared the responses of vascular smooth muscle cells from the two strains to transforming growth factor-beta 1 (TGF-beta 1) and evaluated its potential to account for the different growth properties of these cells in response to a number of vascular-derived growth factors. TGF-beta 1 potentiated the proliferative effects of epidermal growth factor, basic fibroblast growth factor, or the different isoforms of platelet-derived growth factor on vascular smooth muscle cells from SHR but inhibited growth factor-stimulated proliferation of vascular smooth muscle cells from WKY rats. These differential effects of TGF-beta 1 on proliferation could not be attributed to alterations in the expression of the type I, II, or III TGF-beta receptors but appeared more related to the ability of cells to autoinduce the TGF-beta 1 gene. TGF-beta 1 caused a time-dependent increase in its own mRNA levels in vascular smooth muscle cells of WKY rats but attenuated levels in vascular smooth muscle cells of SHR. This effect was specific to TGF-beta 1 autoinduction since similar elevations in TGF-beta 1 mRNA levels were observed when vascular smooth muscle cells from the two rat strains were exposed to phorbol myristate acetate, basic fibroblast growth factor, or platelet-derived growth factor-BB.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 May
PMID:Transforming growth factor-beta 1 gene activation and growth of smooth muscle from hypertensive rats. 817 67

The present study examines the role of serum growth factors in the proliferative response and Na-K-Cl cotransport activity of vascular smooth muscle cells from Milan normotensive (MNS) and hypertensive (MHS) rats. Cells from thoracic aorta of both strains were cultured in 10% serum medium and made quiescent by 72 hours in 0.3% serum medium. MHS cells grown with 10% serum had a shorter population doubling time than MNS cells between passages 8 and 12 (13.8 +/- 1.7 versus 20.1 +/- 1.6 hours, P < .01, n = 4). MHS cells also exhibited a higher response of thymidine incorporation into nucleic acid to serum, epidermal, and platelet-derived growth factor BB. In MHS cells epidermal (100 ng/mL) and platelet (50 ng/mL) growth factors increased thymidine incorporation 2- and 10-fold, respectively. In MNS cells epidermal factor did not induce a significant response, and that of platelet factor was twofold lower than in MHS cells. Binding curves revealed a higher number of receptors for platelet than epidermal growth factor in both strains and a similar number of both receptors in MHS and MNS cells. Quantitative immunoblots of these receptor proteins confirmed the observation that the greater proliferation of MHS cells could not be related to a higher number of growth factor receptors. Cotransport activity (bumetanide-sensitive 86Rb influx in nanomoles per milligram protein per 5 minutes) was found to be significantly higher in MHS cells (16 +/- 3, n = 18) than MNS cells (8 +/- 3, n = 15) at confluence as well as in the log phase of serum-stimulated growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jun
PMID:Cell growth and Na-K-Cl cotransport responses of vascular smooth muscle cells of Milan rats. 820 86

Protein kinase C is an important second-messenger system that is translocated from the cytosol to the cell membrane on cell stimulation. We used confocal microscopy to study the spatial distribution of protein kinase C isoforms after stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor and angiotensin II (Ang II). Monoclonal antibodies for the isoforms alpha and beta were used. Translocation was also assessed by Western blot. Isoform alpha was evenly distributed in the cytosol, whereas the beta isoform formed coarse granules in the perinuclear region. Both isoforms shifted from the cytosolic to the membrane fraction after exposure to Ang II (10(-7) mol/L) and platelet-derived growth factor (100 ng/mL at 6, 12, and 20 minutes). Confocal microscopy showed a rapid assembly of isoform alpha along cytosolic fibers at 6 minutes followed by a translocation toward the nucleus at 12 minutes with Ang II. Platelet-derived growth factor engendered a similar response; however, a cytoskeletal distribution was not observed. The beta isoform was rapidly translocated by both inducers to the perinuclear region and the nucleus. Our results show that inducers cause a translocation of protein kinase C isoforms not only into the cell membrane but also into the cell nucleus. We suggest that protein kinase C may also be important for nuclear signaling.
Hypertension 1994 Jun
PMID:Platelet-derived growth factor and angiotensin II induce different spatial distribution of protein kinase C-alpha and -beta in vascular smooth muscle cells. 820 16

Although pathologic and hemodynamic changes in monocrotaline (MCT)-induced pulmonary hypertension have been studied extensively, relatively little is known about the inter- and intracellular signaling mechanisms underlying such alterations. As a first step to delineating signaling mechanisms governing adverse structural alterations in the hypertensive lungs, we examined changes in the steady-state levels of mRNAs encoding several growth factors including transforming growth factors (TGF), platelet-derived growth factors (PDGF), vascular endothelial cell growth factor (VEGF) and endothelin (ET) as a function of time in MCT-induced pulmonary hypertension in rats. These studies demonstrated a very diverse pattern of growth factor gene expression in response to MCT administration. In general, alterations in the steady-state levels of mRNAs encoding the growth factors preceded the onset of MCT-induced pulmonary hypertension. TGF-beta 1, -beta 2 and -beta 3 transcripts were seen to be elevated, whereas that of TGF-alpha and PDGF-A remained unchanged. Transcripts for PDGF-B and ET were increased in the early stages but declined to less than controls in the latter stages of MCT-induced hypertension. In contrast, levels of VEGF mRNA decreased to less than controls as the disease progressed. Viewed collectively, the diverse pattern of expression suggests that alterations in the levels of the growth factor transcripts may have a significant role in the development of pulmonary hypertensive disease and may be relevant to the pathological and structural changes in MCT-induced pulmonary hypertension.
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PMID:Alterations of growth factor transcripts in rat lungs during development of monocrotaline-induced pulmonary hypertension. 821 53

The lesions of atherosclerosis are initiated as a response to some form of injury to arterial endothelium. Increase in plasma levels of low-density lipoproteins or some components of hyperlipidemic serum may increase the rate of penetration into the artery wall. Monocytes adhere to endothelium, emigrate into the intima and transform into lipid-laden macrophages. The second component of atherogenesis is smooth muscle proliferation in the intima. The proliferating cells originate from cells migrating from the media and from myointimal cells. After adhesion to foci of injury, platelets release platelet-derived growth factor, a potent mitogen for intimal smooth muscle cells. The plaque is increasing, the lumen narrowing. A plaque consisting mainly of yellow, grumous fluid is called an atheroma. The oily content of this plaque is covered by a fibrous cap that is often thin and prone to rupture. An occluding thrombus may result. Lipids and crystalline cholesterol initiate a foreign-body reaction, an inflammatory process. Older lesions are calcified. Examples from the daily work in the mortuary demonstrate the pathogenetic relevance of hypertension, thrombocytes and endothelium.
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PMID:[Morphological basis of atherosclerosis]. 827 97

Carvedilol is a cardiovascular drug currently used for the treatment of hypertension. Clinical studies have recently demonstrated efficacy in angina and congestive heart failure. Recently, carvedilol has been shown to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis induced by a wide variety of growth factors. These findings are of interest since smooth muscle proliferation and abnormal lipid metabolism are proposed to play an important role in the pathogenesis of atherosclerotic plaque formation and in development of stenotic lesions following vascular injury by balloon angioplasty and coronary artery bypass grafting. On the basis of these observations, the antiproliferative actions of carvedilol have been explored in detail. In human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 microM) produced a concentration-dependent inhibition of the mitogenesis stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum, with IC50 values ranging from 0.3 to 2.0 microM. Carvedilol also produced a concentration-dependent inhibition of vascular smooth muscle cell migration induced by platelet-derived growth factor, with an IC50 value of 3 microM. The extensive neointimal formation that occurs following balloon angioplasty of rat carotid arteries was markedly attenuated by carvedilol (1 mg/kg, i.p.; twice daily starting 3 days before angioplasty and continuing until 14 days after angioplasty). Quantitative image analysis demonstrated that carvedilol reduced the neointimal growth following angioplasty by 84% without altering either medial or adventitial cross-sectional areas. These observations indicate that carvedilol may also be effective in the treatment of pathological disorders principally associated with abnormal vascular smooth muscle growth, such as atherosclerosis and acute vascular wall injury induced by angioplasty or coronary artery bypass grafting.
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PMID:Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. 832 99

There is evidence that platelet derived growth factor (PDGF) is a mediator of proliferative changes in renal arteries and mesangium in human disease, in the mesangium in experimental mesangial proliferative glomerulonephritis, and in the interstitium in a rodent model of angiotensin II mediated hypertension. We utilized a monoclonal antibody to the beta-subunit of the PDGF-receptor to localize constitutive expression of this receptor in human and nonhuman primate tissues. Tissues were fixed in cold 2 or 4% paraformaldehyde, and immunohistochemical techniques both at the light microscopic level and immunoelectron microscopy were employed. In the glomerulus, there is widespread expression of this molecule by mesangial cells, and there is frequent expression on the apical and lateral surface of parietal epithelial cells. There is also widespread expression of this molecule by cortical and medullary peritubular interstitial cells, but not by glomerular or peritubular capillary endothelium or other renal parenchymal structures. The identification of receptors capable of binding PDGF B-chain at each of these sites: (1) provides a basis for PDGF mediated mesangial proliferation in human disease; (2) provides a basis for PDGF mediated interstitial cell migration and/or proliferation and/or activation at sites of tubulointerstitial injury; and (3) suggests that glomerular parietal epithelial cells may be responsive to stimulation by PDGF.
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PMID:PDGF-receptor localizes to mesangial, parietal epithelial, and interstitial cells in human and primate kidneys. 844 Dec 24

The endothelium is a physical barrier between the blood and vascular smooth muscle, a source of enzymes activating and deactivating cardiovascular hormones and a site of production of relaxing and contracting factors. In addition, the endothelium is a source of growth inhibitors and promoters of vascular smooth muscle cells. Monoaminooxidase deactivates catecholamines and serotonin. Angiotensin converting enzyme transforms angiotensin I into angiotensin II and breaks down bradykinin into inactive products. Nitric oxide is a potent vasodilator and inhibitor of platelet function that under most circumstances is released together with prostacyclin, which exerts similar effects. Both substances play an important protective role in the coronary circulation in that they cause continuous vasodilation and inhibition of platelet function. In addition, the endothelium is a source of contracting factors such as endothelin-1, thromboxane A2, and endoperoxides. Endothelium-derived growth inhibitors include heparin (sulfates) and transforming growth factor beta 1, while basic fibroblast growth factors and platelet-derived growth factor and possibly endothelin promote proliferation. Because of its strategic anatomic position, the endothelium is a primary target for injuries and cardiovascular risk factors. In particular, aging, low density lipoproteins, hypertension, diabetes, and ischemia alter endothelium function. In arterial coronary bypass grafts, the release of nitric oxide is more pronounced than in vein grafts. Alterations of endothelial function may contribute to vasospasm, thrombus formation, and vascular proliferation and in turn myocardial ischemia, all common events in patients with coronary artery disease.
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PMID:Endothelial dysfunction in coronary artery disease. 847 60

Ciglitazone is the prototype of the thiazolidinedione class of compounds currently being developed for the treatment of insulin resistance and non-insulin-dependent diabetes. The effects of thiazolidinediones on blood pressure and cell calcium metabolism are not well defined. In the obese Zucker rat, a widely studied model of insulin resistance associated with mild hypertension, we investigated the effects of ciglitazone on plasma insulin levels and mean arterial pressure. We also evaluated the effects of ciglitazone on the changes in cytosolic calcium induced by platelet-derived growth factor in A172 human glioblastoma cells and rat A10 vascular smooth muscle cells. Oral administration of ciglitazone, approximately 45 mg/kg per day for 4 weeks, induced significant reductions in plasma insulin levels (p < 0.001) and blood pressure (p < 0.05). Ciglitazone was also found to significantly attenuate the capacity of platelet-derived growth factor BB homodimer to induce sustained increases in intracellular free calcium. These findings suggest that thiazolidinediones may offer a novel pharmacological approach to the treatment of hypertension, and raise the possibility that these compounds may affect blood pressure not only by affecting insulin metabolism but also by modifying the cell calcium response to pressor agents, growth factors, or both.
Hypertension 1993 Jun
PMID:Effects of ciglitazone on blood pressure and intracellular calcium metabolism. 850 86


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