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)

Blood levels of inflammatory markers associated with endothelial dysfunction and atherosclerosis are increased in diabetic patients; the highest levels occur in poorly controlled diabetes. We investigated the activation state of peripheral blood monocytes in diabetes with respect to scavenger receptor (CD36) expression and monocyte chemoattractant protein-1, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and peroxisome proliferator-activated receptors mRNA expression. CD14(+) monocytes were isolated from peripheral blood of type 1 and type 2 diabetic patients with good (HbA(1c) <7.0%) or poor (>9.4%) glycemic control and a group of nondiabetic subjects. Monocytes from diabetic subjects displayed increased CD36 cell surface expression (P < 0.0005) and increased uptake of oxidized LDL (P < 0.05). Monocyte chemoattractant protein-1 gene expression was increased in monocytes from both groups of diabetic subjects (P < 0.05). Both CD68 and peroxisome proliferator-activated receptor-gamma gene expression were increased in the poorly controlled diabetic group (P < 0.05 for each), whose monocytes also displayed increased attachment to endothelial monolayers (P < 0.0005 vs. nondiabetic control subjects). In poorly controlled diabetes, CD14(+) monocytes are functionally activated and show some of the differentiation markers associated with macrophages. These monocytes also demonstrate an increased ability for attachment to normal endothelial cells, one of the early stages in atherogenesis.
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PMID:Activation of peripheral blood CD14+ monocytes occurs in diabetes. 1612 69

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.
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PMID:Macrophage differentiation to foam cells. 1617 64

Smooth muscle cells play an important role in human vascular diseases. Several lines of evidence demonstrate that circulating smooth muscle precursor cells contribute to intimal hyperplasia in animal models. We obtained large spindle cells expressing alpha-smooth muscle actin (alpha-SMA), denoted here as "smooth muscle-like cells" (SMLC), from human peripheral blood mononuclear cells (PBMC). SMLC derived from human PBMC proliferated readily and expressed pro-inflammatory genes during early culture. After long-term culture, SMLC could contract and express characteristic smooth muscle cell markers. We found peripheral blood mononuclear cell expressing alpha-smooth muscle actin in the circulating blood that bore CD14 and CD105. Sorted CD14/CD105 double-positive PBMC could differentiate into SMLC. The number of CD14-CD105-bearing PBMC increased significantly in patients with coronary artery disease compared to patients without coronary artery disease. These results support the novel concept that smooth muscle precursor cells exist in circulating human blood and may contribute to the pathogenesis of vascular diseases.
Atherosclerosis 2006 Aug
PMID:Characterization of smooth muscle-like cells in circulating human peripheral blood. 1625 62

Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-alpha, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.
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PMID:Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly. 1651 51

There is increasing epidemiologic evidence implying a role for chronic infection in atherosclerosis and that microbial TLR agonists may contribute to this disease. Mycoplasma arthritidis is an agent of acute and chronic inflammatory disease in rodents, and has been used extensively as a model for defining the mechanisms involved in arthritis and other inflammatory diseases. We have purified a 28-kDa, apolipoprotein A-1 (apoA-1)-like TLR2-dependent macrophage-activating moiety from a culture of a virulent strain of M. arthritidis. ApoA-1 similarly isolated from uninoculated mycoplasma medium was without bioactivity. The activity of the mycoplasma-derived molecule was resistant to heat and to digestion with proteinase K, but was susceptible to alkaline hydrolysis and H(2)O(2) oxidation. Infrared profiles of normal apoA-1 and that derived from mycoplasma were distinct. Unlike the activity of other mycoplasmal TLR2 agonists such as macrophage-activating lipopeptide-2, activity of the M. arthritidis-derived 28-kDa component was dependent upon CD14, a coreceptor for LPS. Finally, we showed that bioactive lipopeptides prepared from M. arthritidis grown in serum-free medium and also from a 41-kDa known bioactive lipoprotein of M. arthritidis, avidly bound to purified apoA-1 that separated out by SDS-PAGE, induced TNF-alpha and IL-12p40 both in vitro and in vivo. ApoA-1 is a key functional component of the high-density lipoprotein cholesterol complex by scavenging and removing unwanted lipids. Our finding that this molecule can acquire macrophage-activating properties from microbial TLR2-dependent agonists suggests a novel mechanism whereby some microbial agents might reverse the protective role of apoA-1, thus contributing to the genesis of atherosclerosis.
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PMID:A microbial TLR2 agonist imparts macrophage-activating ability to apolipoprotein A-1. 1698 24

Functional C(-260)--> T polymorphism in the promoter of the CD14 gene has been reported to be associated with coronary heart disease (CHD). The functional role of the polymorphism, however, is still a matter of debate, since several studies have not proved its effect on clinical outcomes associated with atherosclerosis. Cardiovascular-related morbidity and mortality was assessed in a post-hoc approach four years after baseline characterization of patients (male/female n = 36/32) with angiographically proven coronary heart disease. CD14 C(-260)--> T promoter genotype was determined at baseline. Seventeen out of 20 CHD patients with non-lethal cardiovascular events carried at least one T-allele. CD14 T-260 allele carriers have a 3.59-fold (95 % confidence interval: 1.11-6.75) increased risk for non-lethal cardiovascular events (Kaplan-Meier plot: log rank test p = 0.029). All patients with lethal outcomes (n = 6) were also T-allele carriers. Multivariate logistic regression analysis among CHD patients including age, established risk factors and the C(-260)--> T polymorphism as covariates and non-lethal events as a dependent variable confirmed the independent prospective effect of the T-allele on cardiovascular outcomes in this subset. Further evidence is provided for the role of CD14 C(-260)--> T promoter polymorphism as a genetic susceptibility marker of atherosclerosis in patients with an advanced clinical course of the disease. Due to the small sample size and post-hoc character of the study large-scale prospective studies that monitor patients with proven CHD are needed to confirm these findings.
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PMID:Post-hoc analysis on the CD14 C(-260)T promoter polymorphism and coronary heart disease. 1708 9

Cardiovascular disease ranks among the leading causes of morbidity and mortality in adult populations in the Western world. Significant progress in understanding the etiology of cardiovascular disease has come from recent recognition that chronic inflammation plays a key role in its development. The principal mediators of this inflammatory response, and the mechanisms by which they work, however, are incompletely understood. Moreover, the complex nature of the inflammatory response poses significant challenges to the development of effective and targeted treatments. Potentially promising targets to reduce inflammation in atherosclerosis include Toll-like receptor (TLR) pathways and anti-inflammatory factors that modulate TLR signaling. In this review, we outline studies that provide insight into the links between cardiovascular disease and inflammation, focusing on innate immunity and endotoxin/TLR4 signaling. We also discuss the contribution of specific host immune/inflammatory responses to atherogenesis, and describe cellular signaling pathways (lipopolysaccharide-binding protein [LBP], CD14, MD-2, TLR4, MyD88, and NF-kappaB, among others) that play key roles in innate immune signaling. Finally, we discuss the therapeutic potential of modulating these cellular signaling pathways as future strategies for the prevention and treatment of cardiovascular disease, including such approaches as specific targeting of the TLR4 signaling pathway, antibiotic therapy, drug classes with broad anti-inflammatory activity (statins, thiazolidinediones), and the potential of vaccine development. Because of the complexity of the links between low-level chronic infections, inflammation, and atherosclerosis, treatment and prevention of cardiovascular disease will likely require an integrated approach that utilizes a combination of these strategies to target the underlying inflammatory processes.
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PMID:Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease. 1710 Jun 25

Systemic lupus erythematosus (SLE) is associated with premature and accelerated atherosclerosis. Circulating progenitor cells (CPCs) are circulating bone-marrow derived cells that play an important role in the repair of vascular damage that underlies the development of atherosclerosis. The objective of this study was to determine the number and functionality of CPCs in patients with SLE. The study included 44 female SLE patients in an inactive stage of disease and 35 age-matched female controls. CPC numbers in the circulation were determined by FACS with monoclonals against CD14, CD34 and CD133. Peripheral blood-derived mononuclear cell (PBMNC) fractions were cultured in angiogenic medium. The endothelial-like phenotype was confirmed and the colony forming unit (CFU) capacity, migratory capacity and the potential to form clusters on Matrigel were determined. Expression of apoptosis inhibiting caspase 8L was analyzed in PBMNCs and CPCs by gene transcript and protein expression assays. The number of CD34-CD133 double-positive cells (P < 0.001) as well as the CFU capacity (P = 0.048) was reduced in SLE patients. Migratory activity on tumor necrosis factor-alpha tended to be reduced in patient CPCs (P = 0.08). Migration on vascular endothelial growth factor showed no significant differences, nor were differences observed in the potential to form clusters on Matrigel. The expression of caspase 8L was reduced at the transcriptional level (P = 0.049) and strongly increased at the protein level after culture (P = 0.003). We conclude that CPC numbers are reduced in SLE patients and functionality is partly impaired. We suggest these findings reflect increased susceptibility to apoptosis of CPCs from SLE patients.
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PMID:Reduced number and impaired function of circulating progenitor cells in patients with systemic lupus erythematosus. 1776 48

Emerging experimental data supports a circulating precursor origin for some smooth muscle cells that participate in vasculogenesis but uncertainty exists on the precise phenotype and lineage of these vascular precursors. We determined the lineage of human smooth muscle outgrowth cells (SOC) derived from circulating blood mononuclear cells and smooth muscle-like cells present in regions of vasculogenesis in diseased arteries. Immunophenotypic characterization of SOC was performed using FACS and immunofluorescence (IF). An SOC hierarchy was determined based on in vitro clonogenic and proliferative potential. Lineage of smooth muscle-like cells in vasculogenic regions in vivo was also determined by dual IF for myeloid and smooth muscle specific markers combined with FISH for the X and Y chromosome in diseased vessel of human subjects who had undergone gender mismatched cardiac transplantation. We show here that primary high proliferative potential smooth muscle outgrowth cells (HPP-SOC) expanded in culture from human peripheral blood mononuclear cells (PBMC) and recipient-derived chimeric smooth muscle cells participating in vasculogenesis in vivo share a myeloid phenotype (CD68 and CD14 positivity). Moreover, HPP-SOC in vitro are distinct in being negative for several myeloid markers such as CD11b, CD13 and CD33, and CD45 surface antigens and chimeric SMC in vivo show no evidence of cell fusion propensity. This study provides evidence of a possible myeloid subpopulation origin for smooth muscle outgrowth cells in blood and vasculogenic smooth muscle-like cells in the intima and adventitial microvasculature of diseased arteries. These data have significant implications for understanding the role myeloid cells play in smooth muscle cell biology and vascular remodelling.
Atherosclerosis 2008 May
PMID:Myeloid lineage of high proliferative potential human smooth muscle outgrowth cells circulating in blood and vasculogenic smooth muscle-like cells in vivo. 1796 71

1. Blood-derived monocytes/macrophages within the intima of the arterial wall are the main source of inflammatory cytokines and factors contributing to lesion growth, plaque instability and thrombotic events. In the present study, we assessed the hypothesis that mRNA expression levels of candidate genes of atherosclerosis in circulating CD14(+) blood monocytes are associated with coronary heart disease (CHD). 2. We investigated mRNA expression levels using reverse transcription-polymerase chain reaction of genes involved in cholesterol uptake (macrophage scavenger receptor (MSR1), scavenger receptor class B member 1 (SRB1), lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1), CD36, LDL receptor (LDLR)), reverse cholesterol transport (apolipoprotein E (ApoE), ATP-binding cassette sub-family A member 1 (ABCA1)) and inflammation (tumour necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), interleukin-6 (IL-6), tissue factor) in CD14(+) monocytes from 119 consecutively recruited patients and found that median CD36 mRNA expression levels were significantly increased in patients with CHD compared with controls (111 x 10(3) vs 96 x 10(3) copies/10(6) copies beta-actin, respectively; n = 79 and 40, respectively; P < 0.05), despite a high interindividual variability in gene expression. 3. A common T --> C polymorphism (rs2151916) located only 14 bp upstream of the upstream transcriptional start site did not influence CD36 expression. 4. Expression levels of the other candidate genes investigated in the present study did not show any statistically significant differences between patients with CHD and controls. 5. We conclude that CD36 mRNA expression is significantly increased in patients with CHD and may serve as an indicator of CHD burden.
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PMID:CD36 mRNA expression is increased in CD14+ monocytes of patients with coronary heart disease. 1806 91


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