UNIPROT:P80098 - FACTA Search

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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

JE is a member of the family of "immediate early" genes induced by growth factors and cytokines. JE encodes a low molecular weight secretory glycoprotein analogous to the human monocyte chemoattractant protein, MCP-1. JE and MCP-1 proteins are thought to play an important role in inflammation and in the recruitment of monocyte/macrophages to the vessel wall during the development of atherosclerosis. We have previously reported that the induction of JE in rat aortic smooth muscle cells (SMC) was specific to platelet-derived growth factor (PDGF) and was not seen with other growth agonists. Using a luciferase reporter system and transient transfection assays of rat aortic SMC, we now report the identification of a region in the proximal rat JE promoter that is responsive to PDGF but not to other growth factors (angiotensin II and alpha-thrombin) or cytokines (interleukin 1-beta and tumor necrosis factor-alpha). The full response to PDGF (approximately 6-fold) requires the cooperative activity of two potentially novel cis-acting elements, at positions -146 to -128 and -84 to -59. While each element produces a different pattern in electrophoretic mobility shift assays, they appear to bind the same PDGF-responsive species. Further analysis of these regions should provide important insights into PDGF-specific responses in vascular SMC.
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PMID:Platelet-derived growth factor-specific regulation of the JE promoter in rat aortic smooth muscle cells. 973

The coexistence of hypercholesterolaemia and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications in patients. A single unifying mechanism of increased production of reactive oxygen species (ROS) by angiotensin II (Ang II) may serve as a causal link between hyperglycaemia and hypercholesterolaemia and many of the major pathways responsible for atherogenic and diabetic disorders. Several lines of evidence suggest a crucial role for Ang II-mediated oxidative stress in the pathogenesis of hyperglycaemia- and hypercholesterolemia-associated endothelial dysfunction. Endothelial dysfunction in these scenarios may be due to impaired nitric oxide (NO) synthesis and/or inactivation of endothelium-derived NO by ROS. That Ang II plays an important role in the development of atherosclerosis and glomerulosclerosis is supported by numerous studies indicating that angiotensin receptor blockers (ARBs) retard the progression of these diseases in both experimental animal models and humans. Evidence indicates that Ang II contributes to atherogenesis at both transcriptional and translational levels by upregulating adhesion molecule mRNA and protein synthesis. The recent demonstration of Ang II AT(2) receptors in the adult kidney and their potential to oppose the vasoconstrictive, antinatriuretic, and profibrotic properties of AT(1) receptors suggests that the balance of intrarenal AT(1) and AT(2) receptors may be important in determining the cellular responses to Ang II in diabetic nephropathy. Results of these studies suggest that hypercholesterolaemia and hyperglycaemia can induce a pro-inflammatory response within coronary arteries and the kidney glomerulus. This response involves production of well described macrophage chemotactic and adhesion molecules, which results in macrophage recruitment and the development of acute and chronic injury. Glomerular macrophage recruitment in experimental diabetes occurs via Ang II-stimulated monocyte chemoattractant protein (MCP)-1 expression, suggesting that the renin-angiotensin system is an important regulator of local MCP-1 expression, and strongly implicating macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury. Diabetes-associated vascular complications may also involve an activation of the nuclear factor (NF)-kappaB by hyperglycaemia. NF-kappaB activation is related to AT(1) receptor-mediated pathways, and is believed to be dependent on activation of the Rho proteins belonging to the superfamily of low molecular weight guanosine triphosphatases (GTPases) that regulate intracellular signalling. Preincubation of vascular smooth muscle cells with insulin doubled NF-kappaB transactivation stimulated by Ang II and hyperglycaemia, suggesting a potential mechanism for crosstalk between the renin-angiotensin system and hyperglycaemia. Taken together, these data suggest that activation of the renin-angiotensin system is a mechanism for the initiation and progression of inflammatory cell infiltration found in early changes common to both hypercholesterolaemia and hyperglycaemia. While the base of information regarding ARBs in high-risk patients with diabetes and hypercholesterolemia is lacking, preclinical and pilot trial data suggest that the ARBs are reno- and vasculoprotective in these patients. Therapeutic blockade of Ang II AT(1) receptors in diabetic and hypercholesterolaemic humans by ARBs, with concomitant elevation in plasma and tissue Ang II levels, may provide vascular and renal protection not only by reducing AT(1) receptor-mediated pro-oxidative effects, but also by unopposed AT(2) receptor stimulation.
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PMID:[Pathophysiological and clinical implications of AT(1) and AT(2) angiotensin II receptors in metabolic disorders: hypercholesterolaemia and diabetes]. 1203 87

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
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PMID:Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. 1296 79

Diastolic heart failure (DHF) has become a social burden; however, evidences leading to its therapeutic strategy are lacking. This study investigated effects of addition of angiotensin II type 1 receptor blocker (ARB) to angiotensin-converting enzyme inhibitor (ACEI) at advanced stage of DHF in hypertensive rats. Dahl salt-sensitive rats fed 8% NaCl diet from age 7 weeks served as DHF model, and those fed a normal chow served as control. The DHF model rats were arbitrarily assigned to 3 treatment regimens at age 17 weeks: ACEI (temocapril 0.4 mg/kg per day), combination of ACEI (temocapril 0.2 mg/kg per day) with ARB (olmesartan 0.3 mg/kg per day), or placebo. At age 17 weeks, this model represents progressive ventricular hypertrophy and fibrosis, relaxation abnormality, and myocardial stiffening. Data were collected at age 20 weeks. As compared with the monotherapy with ACEI, the addition of ARB induced more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening, improvement of relaxation, and inhibition of hemodynamic deterioration. Such benefits were associated with greater decreases in reactive oxygen species (ROS) generation, macrophage infiltration, and gene expression of transforming growth factor (TGF)-beta(1) and interleukin (IL)-1beta, but not with changes in gene expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha. Thus, ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at an advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-alpha.
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PMID:AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure. 1475 77

We tested the hypothesis that blockade of angiotensin II type 1 receptors reduces oxidative stress markers in parallel with urinary albumin and type IV collagen excretions. Sixty-six diabetic patients with nephropathy were randomly assigned to either the angiotensin II receptor blocker (ARB; n=33) or trichlormethiazide (n=33) group. The majority of patients had been treated with angiotensin-converting enzyme inhibitors or calcium channel blockers for > or =1 year before the present study. Reduction of blood pressure was not different between the 2 groups, and HbA1c levels did not change over the study period (8 weeks). Treatment with ARB (candesartan 8 mg/day, n=11 or valsartan 80 mg/day, n=22) for 8 weeks reduced the levels of plasma monocyte chemoattractant protein 1, interleukin 6, urinary 8-epi-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, albumin, and type IV collagen, whereas the levels of these markers were not altered with trichlormethiazide (2 mg/day). Significant correlation was observed between the reduction of the urinary 8-epi- prostaglandin F2alpha and 8-hydroxydeoxyguanosine and those of the urinary albumin and type IV collagen. Subjects with large oxidative stress had large reduction rates because of ARB administration and showed large urinary albumin suppression. These results suggest that ARBs reduce oxidative stress and inflammation in diabetic patients independent of their effects on blood pressure. In addition, increases in oxidative stress caused by angiotensin II may play an important role in the progression of diabetic nephropathy. Our results may help to explain the clinical observation that ARB reduces urinary albumin excretion very efficiently in some patients but not in others.
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PMID:Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy. 1650 7

Platelet-derived growth factor (PDGF) has protean manifestations, including the regulation of growth and migration, in many cell types. We have previously reported that PDGF-BB induces the accumulation of monocyte chemoattractant protein (MCP)-1 mRNA in smooth muscle cells (SMC), in large part due to an increase in mRNA stability. To elucidate the mechanism by which PDGF-BB stabilizes MCP-1 mRNA, we have employed in vitro RNA gel mobility shift and decay assays. Cytoplasmic extracts from PDGF-BB-treated SMC increased the half-life of in vitro transcribed MCP-1 mRNA from approximately 45 min to >2 h. PDGF-BB-inhibitable degradation was not dependent on specific regions of the MCP-1 mRNA and was equally effective on a variety of in vitro transcribed mRNAs. Angiotensin II had a similar effect on MCP-1 mRNA stability, whereas tumor necrosis factor-alpha and basic fibroblast growth factor did not. The PDGF-BB-inhibitable RNAse activity was active at pH 6.6 and heat stable, but was sensitive to proteinase K. Extracts from PDGF-BB- or angiotensin II-treated cells inhibited the RNAse activity of control extracts, suggesting that the effect of PDGF-BB and angiotensin II are due to activation of a soluble inhibitor of the RNAse. The effect of PDGF-BB was blocked by inhibitors of tyrosine phosphorylation, but not by inhibitors of phosphatidylinositol 3-kinase or mitogen-activated protein kinases. These studies provide new insights into the mechanisms by which PDGF-BB enhances mRNA accumulation.
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PMID:PDGF-BB enhances monocyte chemoattractant protein-1 mRNA stability in smooth muscle cells by downregulating ribonuclease activity. 1672 30

Constant mechanical stress is essential for the maintenance of bone mass and strength, which is achieved through the cooperative functions of osteoblasts and osteoclasts. However, it has not been fully elucidated how these cell types mediate mechanical signals. Low-intensity pulsed ultrasound (LIPUS) therapy is a recently developed method for application of mechanical stress, and is used clinically to promote bone fracture healing. In the present study, we applied LIPUS to osteoblasts at different stages of maturation and analyzed their chemokine and cytokine expression. In comparison with their immature counterparts, mature osteoblasts expressed significantly higher levels of mRNAs for the receptor activator of nuclear factor kappa B ligand (RANKL), monocyte chemoattractant protein (MCP)-1, and macrophage-inflammatory protein (MIP)-1beta after a few hours of LIPUS treatment. Intriguingly, protein and mRNA expression of angiotensin II type 1 receptor (AT1), a known mechanoreceptor in cardiomyocytes, was detected in osteoblasts, and the level of expression increased significantly during cell maturation. Furthermore, LIPUS-induced extracellular signal-regulated kinase (ERK) phosphorylation and RANKL/chemokine expression was abrogated by a specific AT1 inhibitor. Thus, AT1 may play one of the essential roles in bone metabolism as a mechanoreceptor of osteoblasts.
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PMID:Low-intensity pulsed ultrasound (LIPUS) induces RANKL, MCP-1, and MIP-1beta expression in osteoblasts through the angiotensin II type 1 receptor. 1716 86

There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
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PMID:Liver fibrosis: a balance of ACEs? 1760 May 27

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions that are, in part, driven by local AT1 receptor (AT1r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT1r blockade (losartan for 8 weeks) on AT1r and AT2r and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor kappaB (NFkappaB), 12-lipooxygenase, cyclooxygenase (COX)-1, COX-2, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (PAI)-1, renal T cell, and macrophage infiltration] as well as renal function and structure. The untreated group exhibited hypertension, deterioration of renal function and structure, reduced or unchanged plasma renin activity, aldosterone concentration, marked up-regulations of AT1r (250%), Ang II-expressing cell count (>20-fold), NAD(P)H oxidase subunits (gp91(phox,) p22(phox), and P47(phox); 20-40%), COX-2 (250%), 12-lipooxygenase (100%), MCP-1 (400%), and PAI-1 (>20-fold), activation of NFkappaB, and interstitial infiltrations of T cells and macrophages in the remnant kidneys. AT1r blockade attenuated the biochemical and histological abnormalities, prevented hypertension, and decelerated deterioration of renal function and structure. Thus, the study demonstrated a link between up-regulation of Ang II/AT1r system and oxidative stress, inflammation, hypertension, and progression of renal disease in rats with renal mass reduction.
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PMID:Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. 1763 6

Interaction between advanced glycation end-products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy pathogenesis. Pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II (Ang II) is also involved in this disease. This study investigated the role of proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity on inhibition of monocyte chemoattractant protein (MCP-1) expression. Telmisartan, an Ang II type 1 receptor blocker, downregulated RAGE mRNA and inhibited superoxide generation and MCP-1 gene expression in mesangial cells; these processes were blocked by GW9662, a PPAR-gamma inhibitor. Candesartan, an Ang II type 1 receptor blocker, did not suppress AGEs-induced superoxide generation. Telmisartan and the antioxidant, N-acetylcysteine, completely inhibited AGEs-induced MCP-1 overproduction by mesangial cells. These results suggest that telmisartan inhibits AGEs-signalling to MCP-1 expression in mesangial cells by downregulating RAGE gene expression and subsequent oxidative stress generation via PPAR-gamma activation. This study has demonstrated a unique benefit of telmisartan in that it may function as an anti-inflammatory agent against AGEs via PPAR-gamma activation and may play a protective role in diabetic nephropathy.
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PMID:Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation. 1769 25

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