Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteopontin (OPN) is a cytokine upregulated in diabetic vascular disease. To better understand its role in vascular remodeling, we assessed how OPN controls metalloproteinase (MMP) activation in aortic adventitial myofibroblasts (AMFs) and A7r5 vascular smooth muscle cells (VSMCs). By zymography, OPN and tumor necrosis factor (TNF)-alpha preferentially upregulate pro-matrix metalloproteinase 9 (pro-MMP9) activity. TNF-alpha upregulated pro-MMP9 in AMFs isolated from wild-type (OPN(+/+)) mice, but pro-MMP9 induction was abrogated in AMFs from OPN(-/-) mice. OPN treatment of VSMCs enhanced pro-MMP9 activity, and TNF-alpha induction of pro-MMP9 was inhibited by anti-OPN antibody and apocynin. Superoxide and the oxylipid product 8-isoprostaglandin F(2) alpha-isoprostane (8-IsoP) were increased by OPN treatment, and anti-OPN antibody suppressed 8-IsoP production. Like OPN and TNF-alpha, 8-IsoP preferentially activated pro-MMP9. Superoxide, 8-IsoP, and NADPH oxidase 2 (Nox2) subunits were reduced in OPN(-/-) AMFs. Treatment of A7r5 VSMCs with OPN upregulated NADPH oxidase subunit accumulation. OPN structure/function studies mapped these activities to the SVVYGLR heptapeptide motif in the thrombin-liberated human OPN N-terminal domain (SLAYGLR in mouse OPN). Treatment of aortic VSMCs with SVVYGLR upregulated pro-MMP9 activity and restored TNF-alpha activation of pro-MMP9 in OPN(-/-) AMFs. Injection of OPN-deficient OPN(+/-) mice with SVVYGLR peptide upregulated pro-MMP9 activity, 8-IsoP levels, and Nox2 protein levels in aorta and increased panmural superoxide production (dihydroethidium staining). At equivalent hyperglycemia and dyslipidemia, 8-IsoP levels and aortic pro-MMP9 were reduced with complete OPN deficiency in a model of diet-induced diabetes, achieved by comparing OPN(-/-)/LDLR(-/-) versus OPN(+/-)/LDLR(-/-) siblings. Thus, OPN provides a paracrine signal that augments vascular pro-MMP9 activity, mediated in part via superoxide generation and oxylipid formation.
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PMID:An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells. 1679 91

Alterations in the vascular angiotensin II system may play a role in the pathophysiology of vascular disease after menopause. In previous studies we have shown that an increase in tumor necrosis factor (TNF)-alpha levels in aging rats because of estrogen deficiency may result in vascular dysfunction. In this study we investigated the effect of TNF-alpha inhibition in angiotensin II modulation of vascular function in aging female animals. Female rats approaching reproductive senescence (12 to 15 months old) were ovariectomized and treated with placebo, estrogen, or a selective TNF-alpha inhibitor (etanercept) for 4 weeks. Expression of angiotensin II in mesenteric arteries was evaluated by immunofluorescence, and the expression of angiotensin-converting enzyme and angiotensin type I receptor (AT(1)R) was investigated by Western immunoblot. Vascular function was assessed in mesenteric arteries using the myograph system, and the role of endogenous angiotensin II on adrenergic vasoconstriction was evaluated in vitro by selective AT(1)R blockade (Candesartan; 10 micromol/L). Our data demonstrate that estrogen-depleted rats have higher serum levels of TNF-alpha and greater sensitivity to phenylephrine vasoconstriction compared with estrogen-replaced animals, which was attenuated by AT(1)R blockade. In vivo TNF-alpha inhibition or estrogen replacement reduced phenylephrine constriction of mesenteric arteries and decreased the modulation of this vasoconstriction by candesartan. These functional changes were accompanied by a reduction in the vascular expression of angiotensin II, angiotensin-converting enzyme, and AT(1)R. These observations indicate that upregulation of TNF-alpha during estrogen deficiency may contribute to enhance vascular constriction by altering the vascular angiotensin II system.
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PMID:Tumor necrosis factor-alpha and vascular angiotensin II in estrogen-deficient rats. 1686 43

Cytokines are peripherally and centrally produced proteins that regulate immune and immunological responses. They also have neurochemical, neuroendocrine and behavioural effects similar to those seen in patients with depression. A review of the literature reveals several cytokines, including IL-1beta, IL-2, IL-6 and IFN, have been shown to be elevated in plasma of working-age adults with depression and dysthymia. A more detailed review of the literature also reveals similar associations between cytokines and late-life depression, with IL-1beta, IL-6 and TNF-alpha all being reported to be elevated in both depression and dysthymia. It has been hypothesized that cytokines provide the link between depression, neurochemical changes and the altered HPA axis that are known to occur in this disease, and evidence is presented that supports this view. However, the evidence that antidepressants may have effects on cytokines is conflicting. Increased cytokine levels may also serve as an explanation for the increased risk for vascular disease that has been associated with depression, and a possible mechanism for this is discussed.
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PMID:Cytokines and late-life depression. 1698 92

Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolytic activity and mediates vascular atherothrombotic disease. Endothelial cells (ECs) synthesize and secrete PAI-1, but the intracellular signaling pathways that regulate PAI-1 expression are not entirely known. We hypothesize that the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway, which regulates endothelial function, could modulate PAI-1 expression in ECs. Cultured bovine aortic and human saphenous vein ECs were stimulated with TNF-alpha, ANG II, insulin, or serum, and PAI-1 expression was determined by Northern and Western analyses. Inhibition of PI3K with wortmannin or LY-294002 enhanced PAI-1 expression induced by these extracellular stimuli. Similarly, overexpression of a dominant-negative mutant of PI3K or Akt increased TNF-alpha- and insulin-induced PAI-1 expression. The increase in PAI-1 was due to transcriptional and posttranscriptional mechanisms as PI3K inhibitors increased PAI-1 promoter activity and mRNA stability. The induction of PAI-1 by TNF-alpha and insulin is mediated, in part, by ERK and p38 MAPK. PI3K inhibitors augmented TNF-alpha- and insulin-induced phosphorylation of these MAPKs. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which is known to activate PI3K/Akt, blocks TNF-alpha- and insulin-induced PAI-1 expression. Treatment with PI3K inhibitors reversed the inhibitor effects of simvastatin on TNF-alpha- and insulin-induced PAI-1 expression. These findings indicate that the PI3K/Akt pathway acts as a negative regulator of PAI-1 expression in ECs, in part, through the downregulation of MAPK pathways. These results suggest that factors that activate the PI3K/Akt pathway in ECs may have therapeutic benefits for atherothrombotic vascular disease.
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PMID:Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. 1717 75

The mechanisms by which isoflavones protect against inflammatory vascular disease remain unclear. Our previous observations suggest that one mechanism involves inhibition of monocyte-endothelial cell interactions in a process that is absolutely dependent on flow. The molecular mechanisms involved and the effects of structurally distinct isoflavones on this process are not known and are investigated herein. Using static and flow-dependent monocyte adhesion assays, our data show that exposure of endothelial cells to biologically relevant concentrations of isoflavones inhibits subsequent TNF-alpha induced monocyte adhesion only during flow. This inhibition involved activating endothelial PPARgamma by stimulating promoter sequences containing the PPARgamma response element by isoflavones and attenuating antiadhesive effects by siRNA targeting of PPARgamma. A comparison of structurally distinct isoflavones suggested a critical role for the A-ring. Using chlorinated derivatives of daidzein, a key structural requirement for PPARgamma agonist activity appears to be the presence of the 7-OH group and the lack of chlorine at the 6- or 8-positions in the A-ring. Collectively, these data support 1) a novel flow-dependent anti-inflammatory mechanism for PPARgamma ligands in vascular endothelial cells and 2) exemplify the current concepts of nutrients modulating disease via regulating specific cell signaling pathways.
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PMID:Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARgamma. 1723 10

Adiponectin (APN) is an adipocyte-derived factor that exists at high concentrations in serum and has anti-inflammatory and systemic vascular-protective properties. In this study, we investigated the role of APN in pulmonary vascular homeostasis. We found that APN localizes to the luminal side of blood vessels in lung and acts in vitro to block TNF-alpha-induced E-selectin upregulation in pulmonary artery endothelial cells. Targeted deletion of the APN gene in mice leads to a vascular phenotype in lung characterized by E-selectin upregulation and age-dependent increases in perivascular inflammatory cell infiltration and pulmonary arterial pressures. Taken together, these findings demonstrate an important role for APN in lung vascular homeostasis and suggest that APN-deficient states may contribute to the pathogenesis of inflammatory pulmonary vascular disease and to the development of pulmonary hypertension.
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PMID:Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. 1956 Nov 37

Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor gamma agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB x NZW)F(1). Ten-week-old prenephritic female NZB/NZW F(1) mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-alpha, IL-1beta, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor gamma agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.
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PMID:The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. 1962 Mar

Auditory dysfunction is related to large/small vessel occlusions and hemorrhage. Sudden sensorineural hearing loss (SSNHL) frequently occurs with anterior inferior cerebellar artery occlusion proximal to the internal auditory artery. Moreover, SSNHL has various pathogenetic mechanisms, the main proposed mechanisms being vascular disease, membrane ruptures, infection, and autoimmunity. Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of cerebrovascular diseases. In the current study, the possible effects of polymorphisms in TNF-alpha and TNF-beta genes on SSNHL are evaluated. Two genetic polymorphisms in the TNF locus (TNF-alpha -308 G - ->A and TNF-beta +252 A - ->G) were investigated as risk factors for SSNHL by determining their prevalence in 97 SSNHL patients and in 587 controls. A significant increase was found for the TNF-beta allele 1 in SSNHL patients compared with the controls (chi( 2) = 7.251, P = .007, odds ratio [OR] = 1.534, confidence interval [CI] = 1.12-2.10). These findings suggest that the TNF-beta +252 locus plays an important role in the etiopathogenesis of SSNHL.
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PMID:Candidate genes of cerebrovascular disease and sudden sensorineural hearing loss. 1983 26

Pro-inflammatory mediators hold important functions in human body in response to infection, trauma and vascular disease. However, their action is down regulated by the release of anti-inflammatory cytokines, thus restoring a balance which reflects the immune status of a given individual. Recent studies have stressed out the importance of circulating levels of cytokines for forensic purposes even if there is a lack of studies regarding the role of post-mortem mucosa-associated lymphoid tissue. In this respect, Peyer's patches (PP), represent one of the most important immunological site of the body and the major component of the gut -associated lymphoid tissue. The aim of this study was to evaluate post-mortem PP immune response in 40 serial autopsy cases of people who died from natural and traumatic death. The study examined spontaneous release of the following cytokines by fresh isolated PP cells: interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, IL-10, IL-6, IL-1 beta, and IL-8. Results will show that higher levels of TNF-alpha, IL-6, IL-1 beta, and IL-8 are statistically correlated with the traumatic death group. From a forensic point of view these data demonstrate that fundamental lymphoid organs, such as PP, may have a potential in diagnosing the cause of death.
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PMID:Post-mortem Peyer's patches: their potential application in forensic medicine. 1987 24

Heme-oxygenase-1 (HO-1), an important enzyme involved in vascular disease, transplantation, and inflammation, catalyzes the degradation of heme into carbon monoxide and biliverdin. It has been reported that overexpression of HO-1 inhibits osteoclastogenesis. However, the effect of HO-1 on osteoblast differentiation is still not clear. We here used adenoviral vector expressing recombinant human HO-1 and HO-1 inducer hemin to study the effects of HO-1 in primary cultured osteoblasts. The results showed that induction of HO-1 inhibited the maturation of osteoblasts including mineralized bone nodule formation, alkaline phosphatase activity and decreased mRNA expression of several differentiation markers such as alkaline phosphatase, osteocalcin, and RUNX2. Furthermore, downstream products of HO-1, bilirubin, carbon monoxide, and iron, are involved in the inhibitory action of HO-1. HO-1 can be induced by H(2)O(2), lipopolysaccharide and inflammatory cytokines such as TNF-alpha and IL-1beta in osteoblasts and also in STZ-induced diabetic mice. In addition, endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin-J2 (15d-PGJ2) markedly increased both mRNA and protein levels of HO-1 in osteoblasts via PI3K-Akt and MAPK pathways. Blockade of HO activity by ZnPP IX antagonized the inhibitory action on osteocalcin expression by hemin and 15d-PGJ2. Our results indicate that upregulation of HO-1 inhibits the maturation of osteoblasts and HO-1 may be involved in oxidative- or inflammation-induced bone loss.
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PMID:Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts. 2002 Apr 68


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