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)

The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-kappaB (NF-kappaB), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-kappaB superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-kappaB and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.
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PMID:Molecular mechanisms of high glucose-induced cyclooxygenase-2 expression in monocytes. 1498 66

C-type natriuretic peptide (CNP) binds and activates the transmembrane guanylyl cyclase B receptor (NPR-B), which decreases vascular tone and inhibits cell proliferation and migration. In contrast, the bioactive lipid sphingosine-1-phosphate (S1P) elicits the opposite physiological effects. Here, we demonstrate a potent acute inhibitory effect of S1P on NPR-B activity in NIH3T3 fibroblasts and A10 vascular smooth muscle cells. In fibroblasts, S1P reduced CNP-dependent cGMP elevations to the same levels as 10% fetal bovine serum, the most potent NPR-B desensitizing agent known. The reduction was dose-dependent (IC50=0.08 micromol/L) and due to decreased NPR-B activity because CNP-dependent guanylyl cyclase activities were markedly diminished in membranes prepared from S1P-treated cells. Similarly, in A10 cells, S1P inhibition was rapid (t1/2=2 to 5 minutes), dose-dependent (IC50=0.3 micromol/L S1P), and mediated by a cell surface receptor. The mechanism of the S1P-dependent desensitization in A10 cells did not require NPR-B degradation or protein kinase C activation, but did require elevated calcium concentrations because a nonspecific calcium ionophore also inhibited NPR-B and an intracellular calcium chelator blocked a significant portion of the S1P response. These are the first data demonstrating cross-talk between the natriuretic peptide and S1P signaling systems. They suggest that the effects of S1P on vascular disease and wound healing may be mediated in part through inhibition of NPR-B.
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PMID:Sphingosine-1-phosphate inhibits C-type natriuretic peptide activation of guanylyl cyclase B (GC-B/NPR-B). 1503 64

Protein kinase C (PKC) has been implicated in the control of vascular tone and mitogenesis in the adult pulmonary vasculature, but little is known about the role of PKC in the neonatal pulmonary vasculature. In addition, the vasodilator nitric oxide (NO) is important in the transition of the pulmonary circulation from fetal to postnatal life, and it is thought that attenuated production of NO and therefore, cGMP may contribute to the pathophysiology of a variety of forms of neonatal pulmonary vascular disease states. Although evidence exists for an interaction between PKC and NO in the adult pulmonary vasculature, the identification of specific roles for PKC in neonatal pulmonary vascular smooth muscle (NPVSM) has not been determined, and no studies have been done on the modulation of cGMP by PKC in NPVSM. Accordingly, immunoblot analysis revealed the expression of the alpha, delta, epsilon, and iota PKC isozymes in NPVSM. Treatment of NPVSM with 10 nM 4-beta phorbol myristate acetate (PMA), a PKC activator, induced translocation of PKCalpha, and PKCdelta from the soluble to the particulate fraction, while exposure to 10 nM endothelin-1 (ET-1), a potent vasoconstrictor and mitogenic substance, caused translocation of PKCdelta and PKCiota from the soluble to the particulate fraction. Sodium nitroprusside (SNP) significantly increased intracellular cGMP levels, an effect attenuated by PMA but not by ET-1. In addition, pretreatment with the specific PKC isozyme antagonist Go 6983 blocked the effect of PMA on cGMP levels. Collectively, these data demonstrate the expression and activation of multiple PKC isozymes in NPVSM, and indicate that PKC inhibits SNP-stimulated cGMP production in NPVSM. These data also suggest that complex intracellular signaling pathways by specific PKC isozymes may be important in the development of neonatal pulmonary vascular function.
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PMID:Protein kinase C modulation of cyclic GMP in rat neonatal pulmonary vascular smooth muscle. 1513 82

Lipoxygenases (LOX) contribute to vascular disease and inflammation through generation of bioactive lipids, including 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE). The physiological mechanisms that acutely control LOX product generation in mammalian cells are uncharacterized. Human platelets that contain a 12-LOX isoform (p12-LOX) were used to define pathways that activate H(P)ETE synthesis in the vasculature. Collagen and collagen-related peptide (CRP) (1 to 10 microg/mL) acutely induced platelet 12-H(P)ETE synthesis. This implicated the collagen receptor glycoprotein VI (GPVI), which signals via the immunoreceptor-based activatory motif (ITAM)-containing FcRgamma chain. Conversely, thrombin only activated at high concentrations (> 0.2 U/mL), whereas U46619 and ADP alone were ineffective. Collagen or CRP-stimulated 12-H(P)ETE generation was inhibited by staurosporine, PP2, wortmannin, BAPTA/AM, EGTA, and L-655238, implicating src-tyrosine kinases, PI3-kinase, Ca2+ mobilization, and p12-LOX translocation. In contrast, protein kinase C (PKC) inhibition potentiated 12-H(P)ETE generation. Finally, activation of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing platelet endothelial cell adhesion molecule (PECAM-1) inhibited p12-LOX product generation. This study characterizes a receptor-dependent pathway for 12-H(P)ETE synthesis via the collagen receptor GPVI, which is negatively regulated by PECAM-1 and PKC, and demonstrates a novel link between immune receptor signaling and lipid mediator generation in the vasculature.
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PMID:Platelet 12-lipoxygenase activation via glycoprotein VI: involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis. 1521 16

Smooth muscle cell (SMC) proliferation has been recognized as central to the pathology of both major forms of vascular disease, atherosclerosis and hypertension. Recently, we reported that ketamine inhibits rat mesangial cell proliferation, suggesting that ketamine inhibits cell growth. Although the IV anesthetic ketamine has been widely used clinically, the exact effects of ketamine on vascular SMC proliferation have not been studied. In this study, we investigated the effects of ketamine on vascular SMC proliferation. Ketamine inhibited [(3)H]thymidine incorporation and decreased the number of SMCs in a concentration-dependent manner (10-200 microM); neither propofol nor fentanyl inhibited [(3)H]thymidine incorporation into human aortic SMCs. The protein kinase C (PKC) inhibitor GF109203x abolished the ketamine-induced inhibition of [(3)H]thymidine incorporation into SMC, but the inhibition was not affected by either the protein kinase A inhibitor H-89 or the protein kinase G inhibitor KT5823. A histological analysis demonstrated the inhibitory effect of ketamine on the intimal thickening of the balloon-injured rat aorta. Based on these results, ketamine inhibits SMCs at clinical concentrations via the PKC pathway. Our results indicate that ketamine might prevent the proliferation of SMCs clinically.
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PMID:The inhibition of aortic smooth muscle cell proliferation by the intravenous anesthetic ketamine. 1550 39

Diabetic vascular disease is characterised by altered vascular reactivity and blood flow, hyperpermeability, hyperproliferative responses, and increased extracellular matrix deposition in tissues that are sites of complications. These vascular functional and structural changes have been linked to excessive glucose metabolism in target organs via at least three pathophysiological mechanisms, including increased sorbitol (polyol) pathway activity, increased nonenzymatic glycation of vascular wall proteins, and increased protein kinase C (PKC) activity. These potential mechanisms of glucose toxicity remain the subject of intense scientific investigation, and therapies targeting each of them are being evaluated in clinical trials. It is becoming increasingly clear that excessive production of growth factors provides a common denominator linking these diverse mechanisms of glucose toxicity to the functional and structural vascular alterations associated with diabetes. Increased expression of vascular endothelial growth factor (VEGF) has been linked to increased metabolism of glucose via the sorbitol pathway, to nonenzymatic glycation, and to increased PKC activity, and appears to modulate the hyperpermeability and hyperproliferative responses of diabetes. Consequently, because of the unmet medical need and market size, numerous pharmaceutical and biotechnology companies have initiated research programmes evaluating growth factor antagonists as a potential therapeutic approach for treating complications associated with diabetic vascular disease. However, before growth factor antagonists can enter clinical testing, a number of important issues must be clarified, including the physiological effect of chronic growth factor inhibition, which appears to be necessary for ameliorating chronic vascular deterioration of diabetes, and administration routes, especially for protein-based therapies.
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PMID:Growth factor antagonists for the treatment of diabetic vascular complications. 1598 71

Chronic complications of diabetes mellitus e.a. diabetic nephropathy, neuropathy and retinopathy develop in at least 30-50% of patients with both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes, and are the major cause of increased morbidity and mortality. The ultimate consequences of diabetes complications include renal failure, foot ulceration and amputation, and blindness. The magnitude of the problem and its economic impact make extremely important to understand the natural history of chronic diabetes complications and to identify more successful preventive and therapeutic options. The pathogenesis of diabetes complications involves multiple mechanisms. The importance of vascular component is well recognized in diabetic retinopathy, which is primarily a vascular disease, as well as diabetic nephropathy developing as a result of complex interplay between hemodynamic and metabolic factors. The importance of vascular versus non-vascular mechanisms in the pathogenesis of diabetic neuropathy remains a subject of debate. Studies in animal and cell culture models revealed that such mechanisms as increased aldose reductase activity, non-enzymatic glycation/glycoxidation, activation of protein kinase C, impaired growth factor support, enhanced oxidative/nitrosative stress, and its downstream effectors such as mitogen-activated protein kinase activation, inflammatory response, endothelin-1 overexpression and impaired Ca(++) signaling, play an important role in all three tissue-targets for diabetes complications i.e. kidney, retina and peripheral nerve. Evidence for important role of the downstream effector of free radical and oxidant-induced DNA injury, poly(ADP-ribose) polymerase activation, is emerging. This review describes recent studies addressing the role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy.
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PMID:Role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy. 1602 23

Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to its toxic forms (various forms of Abeta aggregation), and lastly the oxidative, inflammatory, and other effects of toxic Abeta. Fibrillar beta-amyloid peptide, a major component of senile plaques in AD brain, is known to induce microglial-mediated neurotoxicity under certain conditions, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. Abeta-42 oligomers that are soluble and highly neurotoxic, referred to as Abeta-derived diffusible ligands (ADDLs), assemble under conditions that block fibril formation. These oligomers bind to dendrite surfaces in small clusters with ligand-like specificity and are capable of destroying hippocampal neurons at nanomolar concentrations. Evidence is presented that AD is triggered by these soluble, neurotoxic assemblies of Abeta rather than the late stage pathology landmarks of amyloid plaques and tangles. The premise is that AD symptoms stem from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which nevertheless follows and exacerbates the initial pathologies of AD. The defective clearance of amyloid leads to amyloid angiopathy that in turn perpetuates hypoperfusion that affects formation as well as absorption of CSF thereby altering clearance of amyloid and promoting vascular and parenchymal deposition[1]. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition thus represent a vicious cycle. Chronic vascular hypoperfusion-induced mitochondrial failure results in oxidative damage, which drives caspase 3-mediated Abeta peptide secretion and enhances amyloidogenic APP processing. Intracellular Abeta accumulation in turn promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Abeta generation and oxidation, each accelerating the other. Abeta activates astrocytes that add to the oxidative imbalance, upregulate the expression of APP via TGF-beta, and are capable of expressing BACE1. Each of these 3 actions accelerates the larger cycle of cholinergic neuron destruction. As oxidative stress induces lesions of cholinergic nuclei producing a reduction in cholinergic neurotransmission, a subsequent increase in cortical APP involving PKCepsilon leads to accelerated amyloidogenic APP metabolism. The linkage of cholinergic activation and APP metabolism completes an additional feedback loop wherein the damage wrought by Abeta accelerates further Abeta production. A comprehensive vision of the neuropathophysiologic mechanisms that result in AD reveals several vicious cycles within a larger vicious cycle, that is to say, a number of interactive systems that each, once set in motion, amplify their own processes, thus accelerating the development of AD.
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PMID:Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. 1661 Oct 10

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

Atherosclerosis, restenosis, and the consequences of ischemia are the major causes of morbidity and mortality worldwide. Elucidation of key contributing pathways in animal models of ischemia-reperfusion injury, atherosclerosis, and restenosis consequent to vascular injury may lead to great interest in determining if blocking these pathways could prevent vascular disease in human subjects. This review details the evidence that the protein kinase C (PKC) beta/early growth response-1 axis plays a central role in the response to both acute and chronic vascular stresses in animal models and also indicates the clinical implications of a specific inhibitor of PKCbeta, ruboxistaurin (LY333531).
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PMID:Protein kinase C beta/early growth response-1 pathway: a key player in ischemia, atherosclerosis, and restenosis. 1708 84


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