Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, the effect of 10(-9) to 10(-6) M epinephrine (alpha- and beta-agonist), norepinephrine (alpha- and beta 1-antagonist) isoproterenol (beta-agonist) salbutamol (beta 2-agonist), phenylephrine (alpha 1-agonist) and oxymetazoline (mainly alpha 2-agonist) on DNA synthesis in vascular smooth muscle cells (VSMCs) from rat aorta has been investigated. Our results show that only oxymetazoline induced a moderate dose-dependent elevation of [3H]thymidine incorporation into cell DNA (10(-6) M, 100-300%). Epidermal growth factor (EGF) (50 ng/ml) and platelet-derived growth factor (PDGF)-BB induced an elevation of the [3H]thymidine incorporation into cell DNA from 154 +/- 7 (basal value) to 1270 +/- 95 and 1552 +/- 178 cpm/microgram protein (mean +/- S.D., n = 3). Oxymetazoline (10(-6) M) and phenylephrine induced an increase of [3H]thymidine incorporation to 368 +/- 53 and 205 +/- 27 cpm/microgram protein, respectively. In contrast to phenylephrine, oxymetazoline caused an elevation of the PDGF-BB- and EGF-induced [3H]thymidine incorporation to 1561 +/- 143 and 2086 +/- 235 (means S.D., n = 3), respectively. In addition, EGF (1 to 50 ng/ml) induced a dose-dependent increase of [3H]thymidine incorporation from 154 +/- 7 (basal value) to 486 +/- 35 (1 ng/ml), 912 +/- 74 (5 ng/ml), 1019 +/- 40 (25 ng/ml) and 1270 +/- 95 (50 ng/ml) cpm/microgram protein (mean +/- S.D.). In the presence of 10(-6) M oxymetazoline, 1, 5, 25 and 50 ng/ml EGF caused an increase of [3H]thymidine incorporation to 633 +/- 101, 1124 +/- 87, 1231 +/- 101, and 1561 +/- 89 cpm/microgram protein (mean +/- S.D.).(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1994 Jan
PMID:Oxymetazoline enhances epidermal- and platelet-derived growth factor-induced DNA synthesis. 790 2

Using the [3H]thymidine incorporation technique, the anti-proliferative effects of benidipine, a long-acting calcium antagonist, on porcine cultured vascular smooth muscle cells (VSMCs) were determined and compared with those of other calcium antagonists. Benidipine inhibited serum-stimulated [3H]thymidine incorporation into VSMCs (IC50, 0.2 microM), and this inhibitory effect was significantly more potent than that of nitrendipine, felodipine, nisoldipine, manidipine, amlodipine, nifedipine, verapamil and diltiazem. When growth-arrested cells were stimulated with platelet-derived growth factor followed by insulin, benidipine, administered with either stimulation, inhibited [3H]thymidine incorporation into VSMCs. This suggests that it acts in both the G0/G1 and G1/S phases. In another series of experiments, the anti-proliferative effect in vivo was investigated using rats subjected to balloon catheter-induced endothelial denudation of the aorta. Benidipine (5 mg/kg, p.o., b.i.d.) significantly reduced the incorporation of [3H]thymidine into aortic DNA 48 h after balloon injury, whereas it did not affect incorporation into bone marrow, suggesting that it inhibits arterial DNA synthesis. From our results, benidipine was shown to exert antiproliferative effects on VSMCs in vivo as well as in vitro. The drug may be useful for the treatment of vascular proliferative diseases such as restenosis following percutaneous transluminal angioplasty and atherosclerosis.
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PMID:Anti-proliferative effects of benidipine hydrochloride in porcine cultured vascular smooth muscle cells and in rats subjected to balloon catheter-induced endothelial denudation. 792 Apr 21

Atherosclerosis is a complex disease of uncertain cause. Its pathobiology is believed to represent an abnormal expression of the processes of vascular healing. Etiologic models derive from a 'response to injury' paradigm and can be divided into three separate disease stages: endothelial dysfunction, smooth muscle proliferation and architectural disruption. The initiating event of endothelial dysfunction is unknown, but is believed to be related to low-density lipoproteins and/or their oxidized derivatives. Endothelial injury is signalled to the smooth muscle cells of the media by three routes: direct cell-cell interaction, secretion of soluble growth factors and monocyte-derived cytokines. Monocytes are recruited by the endothelium and invade the subintimal space by a complex interaction of a variety of adhesion proteins and receptors on both cell types. Smooth muscle cell proliferation is initiated by a change in phenotype expression from 'contractile' to 'synthetic' resulting from the binding of fibronectin to specific integrin receptors. Three functionally distinct activities may represent separate subtypes of the 'synthetic phenotype': migration from the media to the intima, increased proliferation and inappropriate extracellular matrix synthesis. The loss of normal regulatory control and anchorage independence of proliferation suggest a relationship to oncogenic transformation. Both migration and proliferation result from the binding of platelet-derived growth factor-like factors to smooth muscle cell receptors, which initiates a cascade of intracellular molecular events leading either to cytoskeletal locomotory restructuring or cell cycle activation. Both pathways also appear to be coregulated by integrin receptors and both depend upon phosphorylation of cell membrane, cytosolic and nuclear regulatory proteins. Clinical expression of atherosclerosis may follow sudden loss of architectural integrity of the intimal plaque by three different mechanisms: plaque fissuring, intraluminal plaque rupture or intramural hemorrhage related to abnormal vessel wall stress and/or biochemistry.
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PMID:Molecular and cellular concepts in atherosclerosis. 793 68

Angiogenesis, the growth and proliferation of blood vessels, may be important in the pathogenesis of atherosclerosis and thus in human atherosclerotic abdominal aortic aneurysms (AAAs). Endothelial migration or chemotaxis is a vital component of the angiogenic response. Here, human aortic endothelial cells (hAECs) were used to investigate the effect of AAA tissue supernatants on hAEC chemotaxis. AAA tissue conditioned media were found to be chemotactic for hAECs. We have previously shown that the angiogenic cytokines interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are present in AAAs and normal aortic explant conditioned media. Currently, we have found that basic fibroblast growth factor (bFGF) and platelet-derived growth factor can also be detected in these supernatants. In order to identify whether some of these soluble mediators contributed to the chemotactic activity of these supernatants, conditioned media were preincubated with either neutralizing anti-IL-8, anti-TNF-alpha, anti-bFGF antibodies or control serum. Anti-IL-8 and anti-TNF-alpha significantly inhibited AAA tissue supernatant-induced hAEC chemotaxis (p < 0.05), while anti-bFGF did not (p not significant). These results indicate that IL-8 and TNF-alpha may be important in chemotactic activity for hAECs in vitro and possibly in AAA neovascularization. The abrogation of angiogenesis using neutralizing antibodies may be a future goal in the therapy of certain disease states such as AAA where angiogenesis plays an important role.
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PMID:Interleukin-8 and tumor necrosis factor-alpha are involved in human aortic endothelial cell migration. The possible role of these cytokines in human aortic aneurysmal blood vessel growth. 794 19

GROWTH-PROMOTING EFFECTS OF ANGIOTENSIN: Angiotensin, a vasoconstrictive peptide, is now known to be an agent of vascular and cardiac growth and may directly influence the pathophysiology of coronary artery disease and ventricular remodeling. Vascular growth occurs when angiotensin activates autocrine and paracrine growth factors, including fibroblast growth factor, transforming growth factor beta-1 and platelet-derived growth factor, and is modulated by endothelium-derived vasodilators and growth inhibitors. ANGIOTENSIN AND CARDIOVASCULAR DISEASE: The presence of angiotensin converting enzyme (ACE) and angiotensin II has been demonstrated in vascular tissue, and these local substances are causally involved in the development of vascular lesions. Similarly, angiotensin can stimulate cardiac myocyte growth and matrix modulation. Cardiac tissue ACE is implicated in ventricular remodeling in the course of progressive heart failure. A genetic variant of the ACE gene has been reported to be associated with increased risks of cardiovascular pathology. ACE INHIBITOR THERAPY: To date, studies of ACE inhibitor treatment in human patients have not demonstrated any prevention of restenosis after angioplasty. However, recent clinical trials in postmyocardial infarction reported that ACE inhibitor therapy reduces recurrent myocardial infarction and prevents cardiac enlargement. Long-term prospective trials are currently being conducted to examine the effects of ACE inhibitor therapy on coronary ischemic events and coronary atherosclerosis, as evaluated by angiography or intravascular ultrasound, and the relationship between coronary events and ACE gene polymorphism.
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PMID:Cell biology and genetics of angiotensin in cardiovascular disease. 796 71

We studied the role of platelet-derived growth factor (PDGF) on the development of atherosclerosis of human coronary arteries of 63 autopsied cases. Smooth muscle cells in fibrocellular intimal thickening lesion showed no significant immunohistochemical reaction of antibodies for PDGF-A or PDGF-B or PDGF-receptor. In atherosclerotic lesions, foam cells derived from macrophages and smooth muscle cells showed intense immunohistochemical reaction with antibodies of PDGF-B and PDGF-receptor, but not with that of PDGF-A. By in situ hybridization, no significant signals of PDGF-A or PDGF-B or PDGF-receptor were demonstrated in proliferating intimal smooth muscle cells in fibrocellular intimal thickening lesions. Uncomplicated atherosclerotic lesions expressed significant amount of m-RNA of c-sis protooncogene and PDGF-B receptor in foam cells. However, no significant signals of PDGF-A were observed in uncomplicated atherosclerotic lesions. These results suggest that foam cells-producing PDGF-B play an important role for the progression of atherosclerotic lesions in human coronary arteries.
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PMID:[Expression of PDGF-A and -B in human coronary atherosclerotic lesion: immunohistochemical and in situ hybridization study]. 796 23

The effect of TFC-612, methyl-6-[(1R,2S,3R)-hydroxy-2-](1E,3S,5R)-3- hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl)thio] hexanoate, on intimal thickening of carotid artery 14 days after endothelium denudation with a balloon catheter was examined in rats. This compound significantly suppressed the neointimal area and the ratio of intimal and medial layer by 41.1% and 31.4%, respectively, at 3.2 micrograms/rat/h s.c. infusion. At this dose, this compound did not inhibit platelet aggregation induced by either collagen or ADP. It did not inhibit bromodeoxyuridine incorporation into medial smooth muscle cells at 3 days after injury. In in vitro experiments, TFC-612 did not inhibit the [3H]thymidine uptake into cultured smooth muscle cells, but it showed significant inhibition of smooth muscle cell migration induced by platelet-derived growth factor (PDGF) at more than 10(-9) M. This compound increased cyclic AMP levels dose dependently in cultured smooth muscle cells at more than 10(-8) M. These results suggest that TFC-612 inhibits intimal thickening by inhibition of smooth muscle cell migration from media to intima through cyclic AMP elevation.
Atherosclerosis 1994 Aug
PMID:Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on intimal thickening after endothelial injury with balloon catheter in rats. 798 Jul 15

The proliferation of vascular smooth muscle cells (SMCs) is a key event in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Polypeptide growth factors are potent SMC mitogens in vitro and are believed to be involved in SMC proliferation in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no low-molecular-weight antagonists of this growth factor have been discovered. We identified a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphthalimide), which inhibits binding of 125I-PDGF BB to cell surface receptors with an IC50 of 0.13 mumol/L. This compound has a lesser effect on the binding of 125I-epidermal growth factor (EGF), 125I-basic fibroblast growth factor (bFGF), or 125I-endothelin to specific cell surface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB- and PDGF AA-stimulated DNA synthesis but not EGF- or bFGF-stimulated DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhibits PDGF-stimulated directional migration and suggest that the compound interacts with PDGF rather than with the receptor. Oral administration of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontaneously hypertensive rats results in significant inhibition of lesion formation in the balloon catheter-deendothelialized carotid artery. These results suggest that SCH 13929 may be a useful tool for understanding the role of PDGF in intimal lesion formation.
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PMID:Inhibition of PDGF receptor binding and PDGF-stimulated biological activity in vitro and of intimal lesion formation in vivo by 2-bromomethyl-5-chlorobenzene sulfonylphthalimide. 801 59

Receptors for the platelet-derived growth factors (PDGFs) are expressed conditionally in developing embryos and adult tissues. Aberrant expression of PDGF receptors is a molecular marker for proliferative disorders such as atherosclerosis, myofibrosis, and malignant astrocytoma. We isolated genomic clones that encompass the 5' end of the mouse PDGF alpha receptor mRNA transcript and extend 10 kb into the upstream flanking region of the gene. Using these clones, we constructed a partial genomic map that locates the promoter and transcription start sites of the gene. One of our genomic clones contains cis-acting regulatory elements that drive expression of reporter gene constructs selectively in cells that express PDGF alpha receptors.
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PMID:Platelet-derived growth factor alpha receptor gene expression: isolation and characterization of the promoter and upstream regulatory elements. 804 46

Effects of two major potent vasoconstrictors, angiotensin II and platelet-derived growth factor, on elastin expression in cultured chick embryonic arterial smooth muscle cells were studied. Platelet-derived growth factor exhibited no effect on elastin synthesis nor its mRNA level but stimulated (1.5-fold) cell proliferation slightly. Angiotensin II inhibited elastin synthesis dose- and time-dependent manner with a maximum suppression of sixty percent of control at a concentration of 10 microM for 18 h treatment. The suppression was accompanied with a comparable decrease in elastin mRNA level. The inhibition was blocked by addition of Sar1,Ala8-angiotensin II and 8-bromo-cGMP. It showed no effect on cell proliferation. Angiotensin II appears to inhibit elastin synthesis through the interaction with its receptor and the modulation of intracellular Ca2+ level. Thus angiotensin II, not platelet-derived growth factor, can exert a profound effect on the extracellular matrix composition in arterial walls, leading to an arterial change in hypertension or atherosclerosis.
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PMID:Elastin synthesis is inhibited by angiotensin II but not by platelet-derived growth factor in arterial smooth muscle cells. 804 11


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