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1.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tissue remodeling processes. TIMP-1 is the main native inhibitor of MMPs and it contributes to the development of tissue fibrosis. It is known that ANG II plays a fundamental role in vascular remodeling. In this study, we investigated whether ANG II modulates TIMP-1 expression in rat aortic smooth muscle cells. In vitro, ANG II induces TIMP-1 mRNA expression in a dose-dependent manner. The maximal increase in TIMP-1 expression was present after 3 h of ANG II stimulation. The ANG II increase in TIMP-1 expression was mediated by the ANG type 1 receptors because it was blocked by losartan. The increase in TIMP-1 expression was present after the first ANG II treatment, whereas repeated treatments (3 and 5 times) did not modify TIMP-1 expression. In vivo, exogenous ANG II was administered to Sprague-Dawley rats (200 ng. kg(-1). min(-1) sc) for 6 and 25 days. Control rats received physiological saline. After treatment, systolic blood pressure was significantly higher (P < 0.01), whereas plasma renin activity was suppressed (P < 0.01), in ANG II-treated rats. ANG II increased TIMP-1 expression in the aorta of ANG II-treated rats both at the mRNA (P < 0.05) and protein levels as evaluated by Western blotting (P < 0.05) and/or immunohistochemistry. Neither histological modifications at the vascular wall nor differences in collagen content in the tunica media were present in both the ANG II- and saline-treated groups. Our data demonstrate that ANG II increases TIMP-1 expression in rat aortic smooth muscle cells. In vivo, both short- and long-term chronic ANG II treatments increase TIMP-1 expression in the rat aorta. TIMP-1 induction by ANG II in aortic smooth muscle cells occurs in the absence of histological changes at the vascular wall.  相似文献   

2.
BACKGROUND: Matrix metalloproteinases (MMPs) are critical for metastasis of tumor cells. Tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural MMP inhibitor, was shown to reduce metastasis in different models. Here, we investigated whether increased TIMP-1 levels in the liver achieved by adenoviral gene transfer will effectively inhibit liver metastasis of two independent tumor cell lines. METHOD: TIMP-1 was transferred with adenoviral vectors into the livers of DBA/2 and Balb/c mice, which were subsequently challenged by hematogenous experimental metastases of the T-cell lymphoma cell line L-CI.5s or the colorectal carcinoma cell line CT-26, respectively. RESULTS: MMP-9 expression in the liver was induced upon metastasis in both tumor types. Adenoviral gene transfer led to high transduction efficacy as indicated by lacZ expression in 60% of hepatocytes. TIMP-1, a key inhibitor of MMP-9, was expressed at 10(5)-fold higher levels by adenoviral gene transfer as compared with levels achieved in TIMP-1 transgenic mice, previously shown to be inefficient to reduce T-cell lymphoma metastasis. High local and systemic (serum) levels of TIMP-1 led to substantial (94%) reduction of T-cell lymphoma and colorectal carcinoma (73%) experimental liver metastasis. CONCLUSIONS: Adenoviral gene transfer led to systemic and local TIMP-1 levels sufficient to inhibit metastasis of a highly aggressive T-cell lymphoma, pointing at the requirement of threshold levels for effective anti-metastatic efficacy. This approach was also efficient in a colon carcinoma solid tumor model. We propose that viral gene transfer of TIMP-1 can provide a suitable defense strategy to prevent metastatic spread to the liver.  相似文献   

3.
Tissue inhibitor of metalloproteinase (TIMP-1) is a natural protease inhibitor of matrix metalloproteinases (MMPs). Recent studies revealed a novel function of TIMP-1 as a potent inhibitor of apoptosis in mammalian cells. However, the mechanisms by which TIMP-1 exerts its anti-apoptotic effect are not understood. Here we show that TIMP-1 activates cell survival signaling pathways involving focal adhesion kinase, phosphatidylinositol 3-kinase, and ERKs in human breast epithelial cells to TIMP-1. TIMP-1-activated cell survival signaling down-regulates caspase-mediated classical apoptotic pathways induced by a variety of stimuli including anoikis, staurosporine exposure, and growth factor withdrawal. Consistently, down-regulation of TIMP-1 expression greatly enhances apoptotic cell death. In a previous study, substitution of the second amino acid residue threonine for glycine in TIMP-1, which confers selective MMP inhibition, was shown to obliterate its anti-apoptotic activity in activated hepatic stellate cells suggesting that the anti-apoptotic activity of TIMP-1 is dependent on MMP inhibition. Here we show that the same mutant inhibits apoptosis of human breast epithelial cells, suggesting different mechanisms of TIMP-1 regulation of apoptosis depending on cell types. Neither TIMP-2 nor a synthetic MMP inhibitor protects breast epithelial cells from intrinsic apoptotic cell death. Furthermore, TIMP-1 enhances cell survival in the presence of the synthetic MMP inhibitor. Taken together, the present study unveils some of the mechanisms mediating the anti-apoptotic effects of TIMP-1 in human breast epithelial cells through TIMP-1-specific signal transduction pathways.  相似文献   

4.
Homocysteine, cytokines (IL-18, IL-6, IL-8) are involved in vascular inflammation and coronary artery disease. Homocysteine influences endothelial IL-6 and IL-8 cytokine expression and release, however, an association between homocysteine and IL-18 has not been previously investigated in endothelial/smooth muscle cells and or in coronary artery disease. We report in 9 coronary artery bypass surgery (CABG) patients a positive correlation r = 0.86 between homocysteine and IL-18 plasma levels (p < 0.05). Plasma IL-18 levels are significantly higher in those patients with elevated homocysteine compared to those with normal levels (p < 0.02; 153 +/- 19 pg/ml versus 116 +/- 14 pg/ml respectively). Our in vitro cell culture studies suggest that the source of IL-18 in CABG patients with elevated homocysteine is not from vascular smooth muscle or endothelial cells.  相似文献   

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Plasma homocysteine is regulated by phospholipid methylation   总被引:2,自引:0,他引:2  
Mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine, a non-protein amino acid, is formed from S-adenosylhomocysteine and partially secreted into plasma. A potential source for homocysteine is methylation of the lipid phosphatidylethanolamine to phosphatidylcholine by phosphatidylethanolamine N-methyltransferase in the liver. We show that mice that lack phosphatidylethanolamine N-methyltransferase have plasma levels of homocysteine that are approximately 50% of those in wild-type mice. Hepatocytes isolated from methyltransferase-deficient mice secrete approximately 50% less homocysteine. Rat hepatoma cells transfected with phosphatidylethanolamine N-methyltransferase secrete more homocysteine than wild-type cells. Thus, phosphatidylethanolamine N-methyltransferase is an important source of plasma homocysteine and a potential therapeutic target for hyperhomocysteinemia.  相似文献   

7.
Although studies have suggested microvessel endothelial cells (MVEC) activation and induction of matrix metalloproteinases (MMPs) by homocysteine (Hcy), the transduction mechanism leading to endothelial activation was unclear. We hypothesized that Hcy induced metalloproteinase and altered the levels of integrin in MVEC. MVEC from mouse brain were isolated and characterized by CD-31 (PECAM-1) FITC labeling. The MVEC were activated with different doses (6-40 microM) of Hcy. The cultured-conditioned-medium was analyzed for MMP activity by gelatin gel-zymography. TIMP-1, -4, beta-1 integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were quantified by Western blot analysis. We used MVEC in cell culture to study the effect of increasing concentrations of Hcy upon the secretion of various proteins into the culture medium. MMP-9, beta-1 integrin, ADAM-12, and TIMP-1 were found in increased concentrations in the culture medium of Hcy-treated cells whereas TIMP-4 was decreased. We have shown that purified TIMP-4 blocked the increase of beta-1 integrin shedding in Hcy-treated cells. Interestingly, our results suggest that TIMP-1 and TIMP-4 function antagonistically in Hcy-induced signaling pathways.  相似文献   

8.
9.
Homocysteine is thought to be a non-protein amino acid. However, in vitro studies suggest that homocysteine is likely to be incorporated by indirect mechanisms into proteins in living organisms. Here I show that homocysteine is a protein amino acid in humans. Homocysteine bound by amide or peptide linkages (Hcy-N-protein) is present in human hemoglobin, serum albumin, and gamma-globulins. 1 molecule of homocysteine per 1000 or 1670 molecules of methionine was present in hemoglobin or albumin, respectively. Other proteins, such as low density lipoprotein, high density lipoprotein, transferrin, antitrypsin, and fibrinogen, contained lower amounts of Hcy-N-protein. In human plasma, levels of Hcy-N-protein represented from 0.3 to 23% of total homocysteine. Thus, Hcy-N-protein is a significant component of homocysteine metabolism in humans, possibly contributing to adverse effects of homocysteine on human cells.  相似文献   

10.
Yamamoto M  Hara H  Adachi T 《FEBS letters》2000,486(2):159-162
Homocysteine is known to be a risk factor for several vascular diseases. Previously, we found a significant association between plasma homocysteine and plasma extracellular-superoxide dismutase (EC-SOD) levels. The binding of EC-SOD to human and bovine aortic endothelial cell cultures showed significant decreases after incubation with 10 microM homocysteine, whereas the expression of EC-SOD in fibroblast cell cultures was inhibited with a high concentration (1 mM) of homocysteine. Furthermore, binding of EC-SOD to heparin immobilized on plates was decreased with homocysteine. These observations suggested that homocysteine decreases the binding of EC-SOD to vascular endothelial cell surfaces by degradation of endothelial heparan sulfate proteoglycan, which results in a loss of the ability to protect endothelial cell surfaces from oxidative stress.  相似文献   

11.
Atherosclerosis is an inflammatory process, triggered by the presence of lipids in the vascular wall, and encompasses a complex interaction among inflammatory cells, vascular elements, and lipoproteins through expression of several adhesion molecules and cytokines. Subendothelial retention of lipoproteins is the key initiating event in atherosclerosis, provoking a cascade of events to pathogenic response. High levels of plasma lipids, particularly low-density (LDL) and very-low-density lipoproteins (VLDL) are among the pathophysiologic stimuli that induce endothelial dysfunction. Endothelial cells regulate coagulation, thrombosis and the fibrinolytic system; the endothelium modulates the activity of smooth muscle cells (vascular tone/proliferation) and controls the traffic of macromolecules and inflammatory cells to the vessel wall. Furthermore, LDLs have been implicated in the induction of changes in permeability, cell adhesion and secretion of vasoactive molecules (nitric oxide [NO]), while VLDLs seem to modulate the fibrinolytic system [tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)]. In this review, we will focus on the pathophysiologic functions of lipoproteins in the vascular wall.  相似文献   

12.
A variety of arachidonic acid metabolites possess the ability to modulate immune cell function. Various inhibitors of arachidonic acid metabolism were compared with regard to their effects on T-suppressor (Ts) cell function. Using staphylococcal enterotoxin B (SEB) to activate Lyt-2+ Ts cells, it was shown that indomethacin and 5,8,11,14-eicosatetraynoic acid (ETYA) inhibit the induction phase, but not the expression phase, of suppressor cell activity. Agents which inhibit thromboxane synthetase or lipoxygenase activities (imidazole, nordihydroguaiaretic acid, and pyrogallol) were not found to affect Ts cell induction. Since inhibitors of prostaglandin synthesis are thought to induce lower levels of cyclic adenosine monophosphate, an attempt to overcome the indomethacin inhibition of Ts cell induction by modulating cyclic adenosine monophosphate levels was made. It was found that theophylline and isoproterenol are not able to overcome the inhibition by indomethacin of Ts cell activity. These results strongly suggest that induction of Ts cells by SEB is dependent on the synthesis of products of the prostaglandin synthetase pathway.  相似文献   

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15.
Hyperhomocysteinemia is associated with an increase in the incidence of vascular diseases, including retinal vascular diseases. We examined the effects of high plasma levels of homocysteine on retinal glial cells and vascular endothelial growth factor (VEGF) expression. Male Sprague-Dawley rats were fed either a 3.0 g/kg homocystine diet or a control diet for 2 week. The homocystine-diet group had higher plasma levels of homocysteine and thiobarbituric acid reactive substances (TBARSs) and lower plasma levels of folate, retinol, alpha-tocopherol, and retinal expression of CuZn superoxide dismutase (SOD) than the controls. The rats fed the homocystine-diet showed an increase in vimentin, glial fibrillary acidic protein (GFAP), and VEGF immunoreactivity in the retina as compared to the controls. The increase in vimentin immunoreactivity in the hyperhomocysteinemic rats was correlated with changes in GFAP immunoreactivity in astrocytes within the ganglion cell layer. We found for the first time that short-term hyperhomocysteinemia-induced oxidative stress activates retinal glial cells and increases VEGF expression in the retina.  相似文献   

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17.
The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.  相似文献   

18.
Stoney CM  Engebretson TO 《Life sciences》2000,66(23):2267-2275
Homocysteine is a sulphur amino acid that is positively associated with risk of vascular disease. Very few behavioral or psychological factors have been studied in relationship to homocysteine levels, despite the fact that several psychological factors have also been linked with risk for cardiovascular disease. One psychological attribute showing a strong association with risk is hostility, which is prospectively predictive of future cardiovascular disease endpoints. Another related psychological factor is anger expression; coronary heart disease risk is associated with both heightened expression and inhibition of anger. The purpose of this study was to test the relationship of hostility and anger expression with homocysteine concentrations in a sample of healthy, middle-aged men and women. Participants completed the Cook-Medley hostility questionnaire, the Speilberger Anger Expression questionnaire, and had blood taken for the assessment of plasma homocysteine concentrations. Results indicated positive and significant associations between hostility and homocysteine levels for all participants, and positive and significant correlations between anger-in and homocysteine levels for men only. These data are among the first to test the relationship between homocysteine and psychological risk factors for cardiovascular diseases, and suggest one potential mechanism for the increased cardiovascular risk associated with hostility and anger expression.  相似文献   

19.
Our aim was to determine if the isolation of cells capable of proliferating in methionine-free homocysteine-containing medium, from the human MeWo-LC1 melanoma tumor cell line which is unable to proliferate or survive under such conditions, was associated with altered growth properties. Cells which were able to proliferate in methionine-free homocysteine-containing medium (homocysteine-responsive cells) were obtained from the homocysteine-nonresponsive MeWo-LC1 cell line after 8 months of continuous exposure to methionine-free homocysteine-containing medium. Unlike the parental MeWo-LC1 cell line, these homocysteine-responsive cells were also able to proliferate normally in methionine-free medium containing 5'-deoxy-5'-methylthioadenosine. In vitro growth rate, methionine requirement, and capacity to form colonies on soft agarose of these homocysteine-responsive cells were reduced compared to those of the homocysteine-nonresponsive parental MeWo-LC1 cell line. Unlike MeWo-LC1, these homocysteine-responsive cells were able to synthesize [3H]S-adenosylmethionine from [3H]adenine and homocysteine. The failure of the MeWo-LC1 cell line to proliferate in methionine-free homocysteine-containing medium may be due to a deficiency in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolic acid. These results indicate that acquisition of a homocysteine-responsive phenotype in homocysteine-nonresponsive malignant human tumor cells is associated with a reduction in the autonomous growth potential of such cells.  相似文献   

20.
The organic solute and steroid transporter (OST/Ost) is a unique membrane transport protein heterodimer composed of subunits designated alpha and beta, that transports conjugated steroids and prostaglandin E(2) across the plasma membrane. Ost was first identified in the liver of the cartilaginous fish Leucoraja erinacea, the little skate, and subsequently was found in many other species, including humans and rodents. The present study describes the isolation of a new cell line, LEE-1, derived from an early embryo of L. erinacea, and characterizes the expression of Ost in these cells. The mRNA size and amino acid sequence of Ost-beta in LEE-1 were identical to that previously reported for Ost-beta from skate liver, and the primary structure was identical to that of the spiny dogfish shark (Squalus acanthias) with the exception of a single amino acid. Ost-beta was found both on the plasma membrane and intracellularly in LEE-1 cells, consistent with its localization in other cell types. Interestingly, arachidonic acid, the precursor to eicosanoids, strongly induced Ost-beta expression in LEE-1 cells and a lipid mixture containing arachidonic acid also induced Ost-alpha. Overall, the present study describes the isolation of a novel marine cell line, and shows that this cell line expresses relatively high levels of Ost when cultured in the presence of arachidonic acid. Although the function of this transport protein in embryo-derived cells is unknown, it may play a role in the disposition of eicosanoids or steroid-derived molecules.  相似文献   

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