Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now recognized that atherosclerosis complications are related to the unstable character of the plaque rather than its volume. Vulnerable plaques often contain a large lipid core, a reduced content of smooth muscle cells, and accumulation of inflammatory cells. Colocalization of macrophages and active matrix metalloproteinases (MMPs) is likely relevant for atherosclerotic lesion disruption. Nevertheless, MMP activity and regulation by cardiovascular drugs remains poorly defined. In this study, we evaluated the effects of avasimibe, fluvastatin, and peroxisome proliferator-activated receptor (PPAR) ligands on 92-kDa gelatinase B (MMP-9) secretion by human THP-1 macrophages. THP-1 macrophages were treated with compounds for 48 h, and secreted MMP-9 protein was quantified by immunoassay. Avasimibe, fluvastatin, and PPARalpha agonists (fenofibric acid and Wy-14643) significantly reduced, in a concentration-dependent manner, MMP-9 protein (up to 67 +/- 5% for fenofibric acid). In these assays, the PPARgamma selective agonist rosiglitazone displayed a lower efficacy than other compounds. Enzymatic activity of MMP-9 was also decreased by all cardiovascular drugs tested. MMP-9 protein/activity inhibition by cardiovascular drugs was due, at least in part, to a decrease in MMP-9 mRNA. These results show that THP-1 macrophages could be an useful cellular model to investigate effects of compounds on plaque vulnerability through MMP-9 activity.
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PMID:Cardiovascular drugs inhibit MMP-9 activity from human THP-1 macrophages. 1516 8

Ischemic disease is a leading cause of death and disability worldwide, and its incidence is expected to increase as the population ages. One population at particularly high risk of developing ischemia is patients with diabetes. Type 2 diabetes is associated with a marked increase in atherosclerosis, stroke and heart attack. Furthermore, the outcome following stroke and heart attack in diabetics is worse than in nondiabetic patients. In recent years, peroxisome proliferator-activated receptor (PPAR) agonists have been found to have potent antiinflammatory actions and have emerged as potential therapies for atherosclerosis and ischemia. The use of these agents is particularly attractive, since two PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), are already used chronically to treat diabetes. In this article we review the role of inflammation in ischemic disease and the biology of PPARs, and summarize the evidence that PPARgamma ligands suppress inflammation with an emphasis on atherosclerosis, and cerebral and myocardial ischemia.
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PMID:Antiinflammatory properties of PPARgamma agonists following ischemia. 1533 71

Obesity is a common and serious metabolic disorder in the developed world that is occasionally accompanied by type II diabetes, atherosclerosis, hypertension, and hyperlipidemia. We have found that mesoderm-specific transcript (Mest)/paternally expressed gene 1 (Peg1) gene expression was markedly enhanced in white adipose tissue of mice with diet-induced and genetically caused obesity/diabetes but not with streptozotocin-induced diabetes, which does not cause obesity. Administration of pioglitazone, a drug for type II diabetes and activator of peroxisome proliferator-activated receptor (PPAR)gamma, in obese db/db mice reduced the enhanced expression of Mest mRNA in adipose tissue, concomitant with an increase in body weight and a decrease in the size of adipose cells. Ectopic expression of Mest in 3T3-L1 cells caused increased gene expression of adipose markers such as PPARgamma, CCAAT/enhancer binding protein (C/EBP)alpha, and adipocyte fatty acid binding protein (aP)2. In transgenic mice overexpressing Mest in adipose tissue, enhanced expression of the adipose genes was observed. Moreover, adipocytes were markedly enlarged in the transgenic mice. Thus Mest appears to enlarge adipocytes and could be a novel marker of the size of adipocytes.
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PMID:Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. 1535 8

A mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene with a cytosine to guanine substitution results in an exchange of proline (Pro) with alanine (Ala) in exon B (codon 12) of this gene. This polymorphism has been associated with high insulin sensitivity and low body weight, but no data have been published to date about its effect on early atherosclerosis. We investigated the relationship of the Pro(12)Ala polymorphism to early atherosclerosis, measured by the intima-media thickness (IMT). A total of 622 subjects were included, aged 40-70 yr, who were participants of the RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study and were at risk of developing type 2 diabetes. Altogether, 449 of the subjects had the common genotype (Pro(12)Pro), 162 had the Pro(12)Ala genotype, and 11 the Ala(12)Ala genotype. IMT was significantly decreased in subjects with the Ala(12)Ala genotype compared with subjects with the other two genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the Ala(12)Ala genotype compared with subjects with the Pro(12)Pro or Pro(12)Ala genotypes. In multivariate analysis, the Ala(12)Ala genotype was a significant independent determinant of IMT. Furthermore, we demonstrated specific expression of the PPARgamma2 gene in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells. In conclusion, our data suggest that the Ala(12)Ala genotype of the PPARgamma2 gene may protect from early atherosclerosis in subjects at risk for diabetes.
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PMID:Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma2 protects against atherosclerosis. 1535 13

Drugs targeting both peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (the thiazolidinediones) and PPAR-alpha (the fibrates) have already been developed for clinical use. However, the thiazolidinediones, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have cardiovascular benefits that have yet to be fully realized. Animal models of atherosclerosis have shown that the thiazolidinediones reduce the extent of atherosclerotic lesions and inhibit macrophage accumulation. Clinical studies have also shown that these drugs improve the lipid profile of patients at risk of developing atherosclerosis and reduce circulating levels of inflammatory markers. This combination of lower lipid concentrations and reduced inflammation may explain the cardiovascular benefits of this class of drugs. Early trials in patients with coronary stents have reported promising findings, with restenosis rates being greatly reduced with thiazolidinedione therapy. It is hoped that the results of future clinical trials will continue to be encouraging, so that the thiazolidinediones' cardiovascular benefits can be fully realized in the clinic.
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PMID:Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting? 1547 Sep 5

Patients with type 2 diabetes are at high risk of cardiovascular disease. In addition to treating hyperglycemia, the thiazolidinedione (TZD) class of antidiabetic agents may also benefit the cardiovascular complications associated with the disease. The two available TZDs, pioglitazone and rosiglitazone, are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists that influence gene expression of key proteins involved in regulating glucose and lipid metabolism. Tumor necrosis factor-alpha (TNF-alpha) and adiponectin are believed to be important in the development of insulin resistance and atherosclerosis. Understanding the role of these cytokines in the inflammatory processes that trigger plaque development might lead to identification of other potential mechanisms that could be exploited to enhance future treatments for patients with diabetes and atherosclerosis.
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PMID:What are the effects of peroxisome proliferator-activated receptor agonists on adiponectin, tumor necrosis factor-alpha, and other cytokines in insulin resistance? 1547 Sep 6

Technologic advances have enhanced clinical understanding of the physical changes that occur in the vasculature during atherosclerosis development. Traditionally, diagnostic techniques such as angiography have focused on the lumen of the coronary arteries, with narrowing of the lumen suggesting the presence of atherosclerotic plaques in the vessel wall. Newer methods, such as intravascular ultrasound, focus on the vessel wall itself and have shown that extensive plaque development can occur in conjunction with minimal luminal restriction of the artery. In fact, lumen narrowing occurs only in the very late stages of atherosclerosis, suggesting that, in many cases, the early stages of disease development would remain undetected when angiographic techniques are used. The ability to detect atheromatous disease, particularly in the early stages of development, must be accompanied by systemic pharmacologic therapies effective in inducing atherosclerotic regression. With this in mind, a recent study in patients treated with statins has shown less progression with aggressive lipid lowering, while the findings from trials employing peroxisome proliferator-activated receptor-gamma agonists are eagerly awaited.
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PMID:Imaging and peroxisome proliferator-activated receptor agonists: uncovering their role in atherosclerosis development. 1547 Sep 7

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-gamma agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-alpha agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-delta and the possibilities for the role of dual-binding agonists are examined.
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PMID:Peroxisome proliferator-activated receptor ligands in atherosclerosis. 1550 Mar 88

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development, including combination therapies, squalene synthase inhibitors, microsomal transfer protein inhibitors, acyl-cholesterol acyl transferase inhibitors, cholesterol ester transfer protein antagonists, peroxisome proliferator-activated receptor agonists, high-density lipoprotein-derived peptides and inflammation inhibitors, which have at least reached trials in animal models. Lipid-altering drugs are likely to to be a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis. New agents will have to show significant advantage in tolerability or efficacy over existing agents and have the potential to be used in combination therapy as is well established for bile acid sequestrants, nicotinic acid or fibrates and statins. Any new drugs will also have to be assessed in clinical end-point trials against current compounds with proven outcome benefits.
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PMID:Lipid-lowering therapies in development. 1550 Mar 89

Obesity frequently promotes a variety of cardiovascular diseases including atherosclerosis, hypertension, and type 2 diabetes. In a view of both the preventive and therapeutic aspects of the abovementioned diseases, most intensive clinical interventions have been primarily directed at decreasing excessive amounts of fat tissue by a change in the balance between intake and expenditure of energy; such changes are typically effected via daily exercise and diet control. Mechanical stimuli such as stretching and rubbing of fat tissues using gymnastic exercises or massage are believed to decrease obesity; however, there is no report concerning the direct effect of the mechanical stimulation on adipocytes. Here, we demonstrated that cyclic stretch inhibited adipocyte differentiation of mouse 3T3-L1 cells, which was attributable to a reduced expression of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)gamma(2) via the activation of an extracellular signal-regulated protein kinase (ERK) pathway. The inhibitory effect of the cyclic stretching on the differentiation of 3T3-L1 cells could be restored by troglitazone, a synthetic ligand for PPARgamma. Our results provide a molecular basis for the physiological significance of the local application of mechanical stimuli to fat tissues, which is totally independent of a mechanism for systemic energy consumption.
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PMID:[Mechanical stretching inhibits adipocyte differentiation of 3T3-L1 cells: the molecular mechanism and pharmacological regulation]. 1550 99


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