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

PPAR(alpha, beta/delta, gamma) are ligand-dependent nuclear receptors and regulate homeostasis, cell proliferation/differentiation and associate with hypolipidemia, atherosclerosis, diabetes, and obesity. Through heterodimerization with retinoid X receptors (RXRs), PPARs bind the same consensus response element, formed by a direct repeat of two AGGTCA hexamers separated by one base. Recently, many PPAR direct and indirect target genes have been reported. Here, we summarize the PPAR direct/indirect target genes, and their functions related to lipid metabolism, adipocyte differentiation.
 ...
PMID:[PPARs target genes]. 1582 22

Dehydroepiandrosterone (DHEA), an adrenal steroid, is known to decrease body fat. Thus, it may also alter the endocrine functions of adipose tissue. The aim of this study was to determine if administration of DHEA might influence adiponectin gene expression and secretion from adipose tissue. We demonstrate here the inducing effect of exogenously administered DHEA on adiponectin gene expression in epididymal WAT and adiponectin levels in serum of rats fed a DHEA-containing diet (0.6%, w/w) for 2 weeks, accompanied by a reduction in epididymal adipose tissue mass. A corresponding increase in peroxisome proliferator-activated receptor gamma (PPAR(gamma)) mRNA expression suggests that PPAR(gamma) may be involved in the up-regulation of adiponectin gene expression after DHEA treatment. The presented observations indicate that the positive effects of DHEA, which seems to play a protective role against insulin resistance and atherosclerosis, may be in fact indirect and due to up-regulation of adiponectin gene expression and stimulation of adiponectin secretion from adipose tissue.
 ...
PMID:Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma. 1590 96

Advanced glycation end-products (AGEs), a group of carbohydrate-derived compounds formed by non-enzymatic glycation and oxidation, are markedly elevated in end-stage renal disease (ESRD) and may be related to both inflammation and oxidative stress. The cellular effects of AGE are largely mediated by their interaction with specific surface receptors, such as RAGE. Measurements of biomarkers of inflammation and oxidative stress were conducted in 7 hemodialysis (HD) patients (5 males) with persistent high-grade inflammation (C-reactive protein [CRP]>10 mg/L) and 11 HD-patients (6 males) with low-grade inflammation (CRP<10 mg/L) for at least 6 months. Measured biomarkers for inflammation included hs-CRP, interleukin (IL)-6, white blood cells, neutrophils, S-albumin, peroxisome proliferator-activated receptors (PPAR alpha, beta, gamma) and nuclear factor kappaB (NFkappaB) activity. Markers for oxidative stress were advanced oxidation products (AOPP), myeloperoxidase (MPO)-activity, pentosidine and carboxymethyl lysine (CML). In addition, the effect of increasing doses of CML-modified human serum albumin on NFkappaB activity was tested in mononuclear cells isolated from each patient. As expected, HD-patients with high-grade inflammation had significantly elevated levels of IL-6 (median 9.2 pg/mL versus 2.5 pg/mL; p<0.01), MPO-activity (134.5+/-14.6 DeltaOD(630)/(min mg protein) versus 80.5+/-12.9 DeltaOD(630)/(min mg protein); p<0.05), PPAR-gamma (0.65+/-0.01 OD(655) versus 0.56+/-0.01 OD(655); p<0.01), and AOPP (269+/-54 microM versus 163+/-15 microM; p<0.05) compared with low-grade inflamed patients. Significant associations were demonstrated between hs-CRP and NFkappaB (rho=0.58; p<0.05), AOPP (rho=0.49; p<0.05) and PPAR-gamma (rho=0.62; p<0.05), respectively. In the patient group with high-grade inflammation, stimulation of mononuclear cells with CML-modified human serum albumin caused a rapid dose-dependent rise (p<0.0001) in NFkappaB activity that could be completely blocked by an anti-RAGE antibody. Inflammation and oxidative stress biomarkers are interrelated in ESRD. Inflammatory cell signal pathways, such as NFkappaB, are activated by CML-modification of proteins via RAGE.
Atherosclerosis 2005 Jun
PMID:Enhanced RAGE-mediated NFkappaB stimulation in inflamed hemodialysis patients. 1591 Aug 60

ATP binding cassette transporter A1 (ABCA1) mediates the cellular efflux of phospholipids and cholesterol to lipid-poor apolipoprotein A1 (apoA1) and plays a significant role in high density lipoprotein (HDL) metabolism. ABCA1's role in the causation of Tangier disease, characterized by absent HDL and premature atherosclerosis, has implicated this transporter and its regulators liver-X-receptoralpha (LXRalpha) and peroxisome proliferator activated receptorgamma (PPARgamma) as new candidates potentially influencing the progression of atherosclerosis. In addition to lipid regulation, these genes are involved in apoptosis and inflammation, processes thought to be central to atherosclerotic plaque progression. A Medline-based review of the literature was carried out. Tangier disease and human heterozygotes with ABCA1 mutations provide good evidence that ABCA1 is a major candidate influencing atherosclerosis. Animal and in vitro experiments suggest that ABCA1 not only mediates cholesterol and phospholipid efflux, but is also involved in the regulation of apoptosis and inflammation. The complex and beneficial interactions between apoA1 and ABCA1 seem to be pivotal for cholesterol efflux. The expression of the ABCA1 is tightly regulated. Furthermore the plaque microenvironment could potentially promote ABCA1 protein degradation thus compromising cholesterol efflux. PPAR-LXR-ABCA1 interactions are integral to cholesterol homeostasis and these nuclear receptors have proven anti-inflammatory and anti-matrix metalloproteinase activity. Therapeutic manipulation of the ABCA1 transporter is feasible using PPAR and LXR agonists. PPAR agonists like glitazones and ABCA1 protein stabilization could potentially modify the clinical progression of atherosclerotic lesions.
 ...
PMID:ABCA1 and atherosclerosis. 1601 95

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition.
 ...
PMID:Dysfunctional fat cells, lipotoxicity and type 2 diabetes. 1603 92

Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL- and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARalpha and PPARgamma agonists, such as thiazolidinediones and fibrates, and PPARdelta agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.
 ...
PMID:Macrophage differentiation to foam cells. 1617 64

Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARalpha is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARalpha controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16(INK4a) (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARalpha activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARalpha activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARalpha inhibits SMC proliferation through p16. Thus, the PPARalpha/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.
 ...
PMID:PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. 1623 70

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
 ...
PMID:PPAR delta: a dagger in the heart of the metabolic syndrome. 1651 91

Several drugs or pharmacologically active molecules such as statins, calcium antagonists, and PPAR agonists have been shown to affect macrophage functions that contribute to atherosclerosis and modulate plaque stability. For example, the modulation of matrix metalloproteinase secretion and cholesterol metabolism in macrophages may help to prevent cardiovascular disease independently of the correction of risk factors.
 ...
PMID:Modulation of macrophage function and metabolism. 1659 19

Activators of metabolic PPAR receptors are used in diabetology and lipidology. Many substance influancing PPAR (beta/delta) are in research. These substances will be perhaps used in obesitology and in atherosclerosis treatment. Much quicker is approaching the use in dermatology. The effect of receptor stimulation will be used in wound healing and in the treatment of allergic and proliferative diseases. Some realeted substancies influencing heterodimers with RXR or RAR receptors are used in the treatment of acne and skin lymfomas. Dermatology will be after internal medicine the second field where influencing of PPAR receptors will be very important.
 ...
PMID:[Metabolic PPAR nuclear receptors and skin]. 1677 Oct 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>