Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the endothelium by inflammatory cytokines is a key event in the pathogenesis of vascular disease states. Proinflammatory cytokines repress the expression of KLF2, a recently identified transcriptional inhibitor of the cytokine-mediated activation of endothelial cells. In this study the molecular basis for the cytokine-mediated inhibition of KLF2 is elucidated. Tumor necrosis factor alpha (TNF-alpha) potently inhibited KLF2 expression. This effect was completely abrogated by a constitutively active form of IkappaBalpha, as well as treatment with trichostatin A, implicating a role for the NF-kappaB pathway and histone deacetylases. Overexpression studies coupled with observations with p50/p65 null cells support an essential role for p65. A combination of promoter deletion and mutational analyses, chromatin immunoprecipitation assays, and co-immunoprecipitation studies indicates that p65 and histone deacetylases 4 cooperate to inhibit the ability of MEF2 factors to induce the KLF2 promoter. These studies identify a novel mechanism by which TNF-alpha can inhibit endothelial gene expression. Furthermore, the inhibition of MEF2 function by p65 and HDAC4 has implications for other cellular systems where these factors are operative.
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PMID:Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases. 1598 6

Vascular calcification is characterized by cellular transdifferentiation and expression of bone-related matrix proteins that result in the presence of bone-like structures in the vascular wall. Interleukin (IL)-4, a pleiotropic cytokine, and osteoprotegerin (OPG), an essential regulator of osteoclast biology, have both been linked to vascular disease. Here, we assessed the role of IL-4 and OPG in vascular calcification in vitro. IL-4 induced OPG mRNA levels and protein secretion by 5-fold in a dose- and time-dependent fashion in human coronary artery smooth muscle cells (CASMC). Activation of the transcription factor STAT6 preceded IL-4-induced OPG expression, and blockade of IL-4-induced STAT6 activation by the phospholipase C inhibitor D609 decreased OPG expression. Long-term exposure of IL-4 for 4 weeks resulted in transformation of CASMC towards an osteoblastic phenotype, based on the expression of the transcription factor Cbfa1 and increased mineral deposition. Notably, calcification of CASMC was inhibited by gene silencing of Cbfa1. During osteogenic transformation, IL-4 down-regulated OPG production in CASMC. IL-4 has differential effects in CASMC: While short-term exposure enhances OPG production through a STAT6-dependent mechanism, long-term exposure causes Cbfa1-dependent osteogenic transformation and a decreased production of OPG, an inhibitor of bone resorption.
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PMID:Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells. 1660 43

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor kappaB (NF-kappaB) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)-alpha-induced NF-kappaB activation and TNF-alpha-induced IkappaB kinase activity. Furthermore, metformin attenuated the TNF-alpha-induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-alpha- and interleukin-1beta-induced NF-kappaB reporter gene expression. AICAR also suppressed the TNF-alpha- and interleukin-1beta-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-kappaB activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.
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PMID:Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. 1663 95

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

Transforming growth factor (TGF)-beta is a multifunctional cytokine involved in the regulation of proliferation, differentiation, migration, and survival of many different cell types. The role of TGF-beta in atherosclerosis has been intensively studied, but the precise function of the downstream signals in this disease entity remains unclear. We recently discovered that mice lacking Smad3, a major downstream mediator of TGF-beta, show enhanced neointimal hyperplasia with decreased matrix deposition in response to vascular injury. This review summarizes the current view on involvement of TGF-beta in atherosclerotic vascular disease and discusses the role of Smad3-dependent TGF-beta signal in vascular response to injury.
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PMID:The role of Smad3-dependent TGF-beta signal in vascular response to injury. 1698 Jan 81

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

Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought. The osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/receptor activator of NF-kappaB ligand (RANKL) cytokine network, a key regulatory system in bone homeostasis, has been implicated recently in vascular calcification, changes in matrix composition and diabetic macroangiopathy, aortic aneurysm development, heart failure and, most importantly, advanced atherosclerosis, plaque destabilization and manifestation of cardiovascular diseases. The concept of an active role of RANKL and OPG in vascular pathophysiology is intriguing and is gaining increasing support from both epidemiological and basic research. OPG serum level is considered to be a stable and reliable indicator of the overall activity of the OPG/RANK/RANKL axis and may find application as a biomarker of vascular risk and prognosis. RANKL in turn may be a suitable target for novel therapies. Pharmacological strategies for specific interference with the OPG/RANK/RANKL axis are currently being developed and evaluated in osteoporosis therapy.
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PMID:The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. 1717 97

Transforming growth factor (TGF)-beta is a multifunctional cytokine with anti-inflammatory, reparative and neuroprotective functions. Increased levels of TGFbeta in Alzheimer disease (AD) are associated with perivascular deposition of extracellular matrix, which may impair clearance of beta-amyloid and contribute to the development of cerebral amyloid angiopathy. TGFbeta signaling is transduced by Smad proteins: on TGFbeta receptor activation, Smads 2 and 3 are released from sequestration by microtubules, phosphorylated (forming pSmad2/3), and, together with Smad 4, translocated to the nucleus, where they initiate the transcription of multiple genes. Neuronal microtubule assembly is disturbed in AD when tau, a microtubule-stabilizing protein, is hyperphosphorylated and forms neurofibrillary tangles. We have investigated the relationship between Ser202 phospho-tau and pSmads 2 and 3 in the temporal lobe in AD. Within neurons in control brains, pSmads 2 and 3 were almost exclusively intranuclear. In AD, pSmad 3 bound to phospho-tau (mostly insoluble tau) and accumulated in the cytoplasm of tangle-bearing neurons; this was accompanied by a marked decrease in nuclear pSmad3. pSmads 2 and 3 were also present in neuronal granulovacuolar inclusions. Our findings suggest that neurofibrillary tangles sequester pSmad3, preventing its translocation into the nucleus and the induction of gene transcription. Interference with the Smad signaling may adversely affect survival of tangle-bearing neurons in AD.
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PMID:Neurofibrillary tangles may interfere with Smad 2/3 signaling in neurons. 1727 1

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
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PMID:The role of protein kinase C activation and the vascular complications of diabetes. 1757 31

The importance of the vascular adventitia is increasingly being recognized not only in vascular disease but also in normal maintenance and homeostasis of vessels. Activation of the adventitia and its resident fibrocytic cells in response to injury, stretch, cytokines, and hormones has been shown to stimulate differentiation, collagen deposition, migration, and proliferation. Importantly, the effects of adventitial fibroblasts are increasingly being ascribed to reactive oxygen species (ROS) produced by adventitial fibroblast NAD(P)H oxidases. Much historical and recent evidence suggests that fibroblast NAD(P)H oxidase) is a harbinger and initiator of vascular disease and remodeling. Data from our laboratory indicate that adventitial fibroblast NAD(P)H oxidase plays a direct and/or paracrine role in neointimal hyperplasia as well as a paracrine role in medial smooth muscle hypertrophy in vivo. We propose that adventitial NAD(P)H oxidase-derived cell-permeant hydrogen peroxide or a byproduct of its oxidation of lipids activates signaling mechanisms in medial smooth muscle leading to the growth response. This review will address the potential role of this adventitial ROS in vascular inflammation and cytokine release to potentiate smooth muscle hypertrophy. We will also survey other signaling pathways involving adventitial NAD(P)H oxidase ultimately leading to changes in vascular phenotype.
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PMID:Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: bellwether for vascular disease? 1768 10


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