UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is one of the risk factors for the progression of atherosclerosis and glomerulosclerosis. Recently, the new oral insulin-sensitizing agent troglitazone has been thought to offer potential in the treatment of diabetes. If adopted for this use, it might be helpful in protecting against the development of atherosclerosis and microvascular complications via its improvement of insulin resistance. However, it has not yet been clarified whether troglitazone acts directly on the vascular cells and inhibits the progression of atherosclerosis, including glomerulosclerosis. Meanwhile, monocyte chemoattractant protein-1 (MCP-1) is known to play an important role in the pathogenesis of atherosclerosis and glomerulosclerosis through the induction of monocyte migration. Therefore, we investigated the effect of troglitazone on the expression of MCP-1 in human mesangial cells (HMCs). HMCs were treated with or without troglitazone (1 or 10 micromol/L) in the presence or absence of tumor necrosis factor alpha (TNF-alpha) at various concentrations (50 or 500 ng/mL), and then MCP-1 secretion from the HMCs was measured. We found that TNF-alpha increased the secretion of MCP-1 by 55-fold versus the control and troglitazone significantly inhibited this TNF-alpha-induced increase in MCP-1 secretion (49.3%). Moreover, Northern blot analysis showed that troglitazone decreased the MCP-1 mRNA level in HMCs. We demonstrated that alpha-tocopherol also inhibited TNF-alpha-induced MCP-1 production in HMCs, although its effects were not as strong as troglitazone. The present study indicates that troglitazone may prevent the progression of atherosclerosis by inhibiting MCP-1 expression in mesangial cells.
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PMID:Inhibitory effect of troglitazone on tumor necrosis factor alpha-induced expression of monocyte chemoattractant protein-1 in human mesangial cells. 1069 Sep 39

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.
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PMID:Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. 1069 53

Lipoproteins modified by oxidation, glycation, alkylation, and nitration are generated by oxidative stress during inflammation, diabetes, and inadequate supply of dietary antioxidants. A family of genes, the scavenger receptors, recognizes and internalizes modified lipoproteins, making them susceptible to degradation. Clearance of modified lipoproteins by scavenger receptors occurs mainly in macrophages, dendritic cells, and Kupffer cells of the liver. However, scavenger receptor expression also occurs in other cells, such as endothelial cells, aortic smooth muscle cells, neuronal cells, and keratinocytes. Thus, the local clearance of oxidized low-density lipoprotein and the resolution of inflammatory processes may rely in part on the expression of scavenger receptors in "nonprofessional" phagocytes. Uptake of oxidized low-density lipoprotein, without an efficient machinery to degrade them and uncontrolled expression of scavenger receptors, may lead to cellular deregulation, apoptosis, and formation of foam cells. Diseases accompanied by oxidation of lipoproteins, such as atherosclerosis, Alzheimer disease, glomerulosclerosis, ataxia with vitamin E deficiency, and possibly age-dependent lipofuscin deposition, may share a common pathogenetic feature. This review will focus on foam cell formation, mainly within the atherosclerotic lesion, and the possible involvement of aberrant regulation of the scavenger receptor genes. To date, the regulatory mechanisms at the basis of scavenger receptor gene expression and their roles in atherosclerosis and other diseases are not well established. Knowledge on this subject could lead to a better understanding of the pathogenesis, prevention, and therapy of these diseases.
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PMID:Scavenger receptors and modified lipoproteins: fatal attractions? 1090 71

Oxidized low-density lipoprotein (OxLDL) has been implicated in atherosclerosis and glomerulosclerosis. LOX-1 is a recently identified OxLDL receptor that is abundantly expressed in vascular endothelial cells. The aim of the present study was to investigate LOX-1 expression in the kidneys of hypertensive rats. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were fed a 0.3% or 8% NaCl diet. Some DS 8% rats were treated with manidipine or hydralazine. LOX-1 gene expression was markedly elevated in the kidneys and glomeruli of hypertensive DS 8% rats compared with those of normotensive DR and DS 0.3% rats. Prolonged salt loading further increased the renal LOX-1 expression in DS rats. The LOX-1 upregulation in DS 8% rats was accompanied by renal overexpression of transforming growth factor-beta 1 and type I collagen, impaired renal function, and histologic glomerulosclerotic changes, all of which were ameliorated by antihypertensive treatment. LOX-1 was indeed expressed in the glomeruli in vivo and in cultured glomerular cells in vitro. However, LOX-1 expression was elevated in the aorta but not the kidneys of spontaneously hypertensive rats, which exhibited hypertension but minor glomerulosclerotic changes. In conclusion, the LOX-1 upregulation in the kidney of DS 8% rats was parallel to glomerulosclerotic changes and renal dysfunction, suggesting a possible pathogenetic role for renal LOX-1 in the progression to hypertensive glomerulosclerosis.
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PMID:Expression of LOX-1, an oxidized low-density lipoprotein receptor, in experimental hypertensive glomerulosclerosis. 1100 13

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease marked by immune-complex mediated lesions in small blood vessels of various organs, especially the kidneys, although other factors may also be implicated in the pathogenesis of the disease. This article focuses on the role of lipids in the progression of glomerular, vascular and tubulo-interstitial lesions in two patients with lupus nephritis associated with pronounced hyper- and dyslipidemia. The pathogenesis of progressive glomerulosclerosis in both patients appears to be multifactorial. In addition to immune complex mediated lupus glomerulonephritis, progressively active in the first patient, severe nephrotic-range persistent proteinuria, arterial hypertension associated with hyperfiltration and hyperperfusion injuries and, to a minor extent, hyper- and dyslipidemia were observed. Immunological and non-immunological factors were shown to contribute to the development of tubulo-interstitial lesions. In both patients, in addition to local immune deposits, prominent tubulo-interstitial lipid deposits were probably causally related to both hyperlipidemia and the increased permeability of the glomerular filtration barrier. Tubular lesions were highlighted by intracytoplasmic lipid droplets as well as small cleft-like spaces found to be impacted in the tubular lumina. They were seen to penetrate tubular epithelial cells and eventually lodge in the interstitium, surrounded by mononuclear cell infiltrates and foam cells. In both patients, hypertensive angiopathy and extraglomerular vascular immune deposits were demonstrated. In addition, in the second patient, arteriolar and small arterial hyaline was found at the age of 28 years to be full of lipids and calcium precipitates, suggesting a peripheral atherosclerosis-like process which never occurs as a natural age-related condition. In conclusion, all parts of the nephron may be involved in the pathogenetic process causally related or influenced by hyper- or dyslipidemia. Associated either with endothelial cell injury and consequent insudation of lipids in the vascular walls, glomerular filtration barrier injury with hyperfiltration, or tubulo-interstitial lipid deposition, the mechanism of tissue damage by lipids in all parts of the nephron shares similarities with the pathogenesis of systemic atherosclerosis.
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PMID:Role of lipids in the progression of renal disease in systemic lupus erythematosus patients. 1102 Sep 63

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

Aging is an independent risk factor for cardiovascular and renal disease. The study reported here investigated whether aging affects endothelin-1 (ET-1) and tissue levels of the nitric oxide metabolites nitrite/nitrate in the kidney of rodents. Blood pressure was measured by the tail-cuff method, ET-1 protein was determined by radioimmunoassay/high-performance liquid chromatography (RIA/HPLC) and nitrite/nitrate was measured by ion-pairing chromatography. Compared to young male Wistar Kyoto rats (3 months of age), renal ET-1 protein levels in whole kidneys increased 3.6-fold at 24 months of age (from 70 +/- 9 to 253 +/- 43 pg/g tissue, p < 0.05, n = 6 each group). Similarly, renal ET-1 protein increased 1.7-fold in 18-month-old C57BL/6J mice as compared to 8-month-old adult animals (from 188 +/- 18 to 319 +/- 14 pg/g tissue, p < 0.05, n = 5-7). In female RoRo-Wistar rats (6, 18 and 33 months of age), tissue nitrite/nitrate levels in whole kidneys decreased with increasing age (from 232 +/- 25 to 130 +/- 6 micromol/l/g tissue, p < 0.05). Thus, aging in healthy rodents is associated with a marked upregulation of renal ET-1 protein content and a decrease in tissue nitrite/nitrate levels in whole kidneys, independent of blood pressure. Activation of the ET pathway with aging may promote the development of age-dependent diseases such as glomerulosclerosis, hypertension and atherosclerosis.
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PMID:Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: implications for the age-dependent increase of cardiorenal disease. 1107 64

Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal failure (ESRF) in children. Our previous studies have shown that Arab children in Israel have a worse prognosis compared with Jewish patients despite similar clinical presentation and management. Progression of proteinuric glomerular diseases has been associated with alterations in lipid metabolism, and similarities have been drawn between the mechanisms underlying atherosclerosis and glomerulosclerosis. Paraoxonase (PON) is a high-density lipoprotein (HDL)-associated enzyme involved in preventing the oxidation of low-density lipoprotein (LDL), and an association has been shown between two genetic polymorphisms in PON1 and the risk of coronary artery disease. The aim of this study was to determine the frequency of these genetic polymorphisms in PON1 in Arab and Jewish children with FSGS and to determine any association with severity of outcome. Forty-seven children (21 Arab and 26 Jewish) with biopsy-proven FSGS and 274 healthy controls of matching ethnic origin were studied. The glutamine (A)-192-arginine (B) and the methionine (M)-55-leucine (L) polymorphisms were analyzed. The frequency of the A allele was similar in patients and controls (0.68 versus 0.71), as was that of the L allele (0.63 versus 0.6). When subgroups were analyzed, the prevalence of the LL genotype in Arab patients was significantly greater than in Jewish patients (57.1% versus 26.9%, P: < 0.05) and Arab controls (57.1% versus 28.9%, P: < 0.03). A trend in association was found between homozygosity for the L allele and progression of renal disease in Arab children. Homozygosity for the L allele is a risk factor for developing FSGS in Arab children and may be associated with a worse prognosis.
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PMID:Genetic polymorphism in paraoxonase is a risk factor for childhood focal segmental glomerulosclerosis. 1109 50

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.
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PMID:Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice. 1127 14

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress, and static pressure are possible regulatory elements in CTGF expression. In this study, we examined the ability of static pressure to modulate CTGF gene expression in cultured human mesangial cells. Low static pressure (40-80 mm Hg) stimulated cell proliferation via a protein kinase C-dependent pathway. In contrast, high static pressure (100-180 mm Hg) induced apoptosis in human mesangial cells. This effect was reversed by treatment with CTGF antisense oligonucleotide but not with transforming growth factor beta1-neutralizing antibody or protein kinase C inhibitor. High static pressure not only up-regulated the expression of CTGF, but also the expression of extracellular matrix proteins (collagen I and IV, laminin). This up-regulation of extracellular matrix proteins was also reversed by treatment with CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes, including apoptosis-associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation of a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cells by transient transfection had similar effects. Taken together, these results suggest that high blood pressure up-regulates CTGF expression in mesangial cells. High levels of CTGF in turn enhance extracellular matrix production and induce apoptosis in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis.
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PMID:Static pressure regulates connective tissue growth factor expression in human mesangial cells. 1127 31

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