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 critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial wall of arteries, and their transformation from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). To define genes that are specifically expressed during the transformation of macrophages into foam cells, we have performed a subtractive library screening utilizing mRNA isolated from THP-1 macrophages and foam cells. From this analysis, we have identified adipocyte lipid binding protein (ALBP/aP2) as a gene that is highly upregulated in foam cells in response to oxLDL. Furthermore, overexpression the ALBP gene using an adenovirus construct enhanced the accumulation of cholesterol ester in macrophage foam cells, probably due to an increase in transcription since oxLDL enhanced ALBP promoter activity in experiments using a promoter-luciferase reporter gene construct. The induction of ALBP by oxLDL probably involved activation of peroxisome proliferator-activated receptor gamma (PPARgamma) transcription factors, since four different endogenous PPARgamma ligands, including 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE), two oxidized lipid components of oxLDL, as well as 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and retinoic acid (RA), all induced ALBP expression in macrophage/foam cells. Finally, ALBP was found to be highly expressed in vivo in macrophage/foam cells of human atherosclerotic plaques. These observations suggest that oxLDL-mediated increase in ALBP gene expression accelerate cholesterol ester accumulation, and that this is an important component of the genetic program regulating conversion of macrophages to foam cells. The observation that ALBP is readily detected in foam cells in active atherosclerotic lesions implicates a role for ALBP in human vascular disease. The induction of ALPB expression by oxLDL likely involves activation of PPARgamma by components of oxLDL (9-HODE and 13-HODE) that also function as PPARgamma ligands. Our results add to the concern that the clinical use of insulin-sensitizing PPARgamma agonists (i.e. thiazolidinediones) to treat Type 2 Diabetes could exacerbate atherosclerosis, and highlight the need for clinical trials that address this issue.
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PMID:The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. 1241 76

Peroxisome proliferator-activated receptors (PPAR)alpha, gamma and beta/delta belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARalpha, gamma and beta/delta subtypes have significant differences in their ligand and gene specificities. PPARalpha is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARgamma is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Delta12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARgamma is a key regulator of glucose homeostasis and adipogenesis. PPARbeta/delta ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARalpha (fibrates) and PPARgamma (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease.
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PMID:Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. 1678 10

Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-kappaB (NF-kappaB) by multiple mechanisms (IkappaB kinase inhibition and blockade of NF-kappaB nuclear binding) and activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Prostaglandin F2alpha (PGF2alpha) may also have important anti-inflammatory effects, although current data are limited. In animal models, expression of both PGD and PGF synthases declines during acute inflammation, only to rise again during the resolution phase, suggesting their possible role in resolving inflammation. Prostaglandin E2 (PGE2), the classic model of a proinflammatory lipid mediator, also has anti-inflammatory effects that are both potent and context dependent. Thus, accumulating data suggest that PGs not only participate in initiation, but may also actively contribute to the resolution of inflammation. Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process.
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PMID:The anti-inflammatory effects of prostaglandins. 1924 Jun 48