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Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling.
Vogel ME, Idelman G, Konaniah ES, Zucker SD
(2017) J Am Heart Assoc 6:
MeSH Terms: Animals, Antioxidants, Aorta, Bilirubin, Cell Movement, Collagen, Diet, Western, Intercellular Adhesion Molecule-1, Lipid Metabolism, Lymphocytes, Male, Mice, Mice, Knockout, Monocytes, Plaque, Atherosclerotic, Receptors, LDL, Signal Transduction, Vascular Cell Adhesion Molecule-1
Show Abstract · Added April 27, 2017
BACKGROUND - Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient ( ) mice and elucidate the molecular processes underlying this effect.
METHODS AND RESULTS - Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression.
CONCLUSIONS - Bilirubin suppresses atherosclerotic plaque formation in mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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18 MeSH Terms
Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation.
Capozzi ME, Hammer SS, McCollum GW, Penn JS
(2016) Sci Rep 6: 39211
MeSH Terms: 8,11,14-Eicosatrienoic Acid, Adamantane, Animals, Cells, Cultured, Disease Models, Animal, Down-Regulation, Endothelial Cells, Epoxy Compounds, Fatty Acids, Unsaturated, Humans, Intercellular Adhesion Molecule-1, Lauric Acids, Male, Mice, Retinal Vasculitis, Retinal Vessels, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1
Show Abstract · Added April 10, 2019
The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.
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MeSH Terms
NFAT isoforms play distinct roles in TNFα-induced retinal leukostasis.
Bretz CA, Savage SR, Capozzi ME, Suarez S, Penn JS
(2015) Sci Rep 5: 14963
MeSH Terms: Animals, Cell Adhesion, Cells, Cultured, Chemokine CCL2, Chemokine CX3CL1, Chemokine CXCL10, Chemokine CXCL11, Disease Models, Animal, E-Selectin, Endothelial Cells, Enzyme-Linked Immunosorbent Assay, Gene Expression, Humans, Intercellular Adhesion Molecule-1, Leukostasis, Male, Mice, Inbred C57BL, NFATC Transcription Factors, Protein Isoforms, RNA Interference, Retinal Diseases, Retinal Vessels, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1
Show Abstract · Added April 10, 2019
The objective of this study was to determine the role of individual NFAT isoforms in TNFα-induced retinal leukostasis. To this end, human retinal microvascular endothelial cells (HRMEC) transfected with siRNA targeting individual NFAT isoforms were treated with TNFα, and qRT-PCR was used to examine the contribution of each isoform to the TNFα-induced upregulation of leukocyte adhesion proteins. This showed that NFATc1 siRNA increased ICAM1 expression, NFATc2 siRNA reduced CX3CL1, VCAM1, SELE, and ICAM1 expression, NFATc3 siRNA increased CX3CL1 and SELE expression, and NFATc4 siRNA reduced SELE expression. Transfected HRMEC monolayers were also treated with TNFα and assayed using a parallel plate flow chamber, and both NFATc2 and NFATc4 knockdown reduced TNFα-induced cell adhesion. The effect of isoform-specific knockdown on TNFα-induced cytokine production was also measured using protein ELISAs and conditioned cell culture medium, and showed that NFATc4 siRNA reduced CXCL10, CXCL11, and MCP-1 protein levels. Lastly, the CN/NFAT-signaling inhibitor INCA-6 was shown to reduce TNFα-induced retinal leukostasis in vivo. Together, these studies show a clear role for NFAT-signaling in TNFα-induced retinal leukostasis, and identify NFATc2 and NFATc4 as potentially valuable therapeutic targets for treating retinopathies in which TNFα plays a pathogenic role.
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MeSH Terms
The effects of stress at work and at home on inflammation and endothelial dysfunction.
Non AL, Rimm EB, Kawachi I, Rewak MA, Kubzansky LD
(2014) PLoS One 9: e94474
MeSH Terms: Aged, Biomarkers, Endothelium, Vascular, Health Personnel, Humans, Inflammation, Intercellular Adhesion Molecule-1, Interleukin-6, Life Change Events, Male, Middle Aged, Receptors, Tumor Necrosis Factor, Stress, Psychological, Vascular Cell Adhesion Molecule-1, Workload
Show Abstract · Added January 20, 2015
This study examined whether stress at work and at home may be related to dysregulation of inflammation and endothelial function, two important contributors to the development of cardiovascular disease. In order to explore potential biological mechanisms linking stress with cardiovascular health, we investigated cross-sectional associations between stress at work and at home with an inflammation score (n's range from 406-433) and with two endothelial biomarkers (intercellular and vascular adhesion molecules, sICAM-1 and sVCAM-1; n's range from 205-235) in a cohort of healthy US male health professionals. No associations were found between stress at work or at home and inflammation. Men with high or medium levels of stress at work had significantly higher levels of sVCAM-1 (13% increase) and marginally higher levels of sICAM-1 (9% increase), relative to those reporting low stress at work, independent of health behaviors. Men with high levels of stress at home had marginally higher levels of both sVCAM-1 and sICAM-1 than those with low stress at home. While lack of findings related to inflammation are somewhat surprising, if replicated in future studies, these findings may suggest that endothelial dysfunction is an important biological mechanism linking stress at work with cardiovascular health outcomes in men.
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15 MeSH Terms
Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue.
Camell C, Smith CW
(2013) PLoS One 8: e75147
MeSH Terms: Adipose Tissue, Animals, Cell Proliferation, Dietary Fats, Unsaturated, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Intercellular Adhesion Molecule-1, Macrophages, Male, Mesentery, Mice, Mice, Inbred C57BL, Oleic Acid, Real-Time Polymerase Chain Reaction
Show Abstract · Added July 21, 2014
Several studies have implicated fatty-acids as inflammatory regulators, suggesting that there may be a direct role for common dietary fatty-acids in regulating innate immune cells. In humans, a single high-fat meal increases systemic cytokines and leukocytes. In mice, short term high-fat feeding increases adipose tissue (AT) leukocytes and alters the inflammatory profile of AT macrophages. We have seen that short term high fat feeding to C57BL/6J male mice increases palmitic and oleic acid within AT depots, but oleic acid increase is highest in the mesenteric AT (MAT). In vitro, oleic acid increases M2 macrophage markers (CD206, MGL1, and ARG1) in a murine macrophage cell line, while addition of palmitic acid is able to inhibit that increase. Three day supplementation of a chow diet, with oleic acid, induced an increase in M2 macrophage markers in the MAT, but not in the epididymal AT. We tested whether increases in M2 macrophages occur during short term ad lib feeding of a high fat diet, containing oleic acid. Experiments revealed two distinct populations of macrophages were altered by a three day high milk-fat diet. One population, phenotypically intermediate for F4/80, showed diet-induced increases in CD206, an anti-inflammatory marker characteristic of M2 macrophages intrinsic to the AT. Evidence for a second population, phenotypically F4/80(HI)CD11b(HI) macrophages, showed increased association with the MAT following short term feeding that is dependent on the adhesion molecule, ICAM-1. Collectively, we have shown that short term feeding of a high-fat diet changes two population of macrophages, and that dietary oleic acid is responsible for increases in M2 macrophage polarization.
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14 MeSH Terms
Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community.
Schnabel RB, Yin X, Larson MG, Yamamoto JF, Fontes JD, Kathiresan S, Rong J, Levy D, Keaney JF, Wang TJ, Murabito JM, Vasan RS, Benjamin EJ
(2013) Arterioscler Thromb Vasc Biol 33: 1728-33
MeSH Terms: Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Disease-Free Survival, Female, Health Surveys, Humans, Incidence, Inflammation, Inflammation Mediators, Intercellular Adhesion Molecule-1, Interleukin-6, Male, Massachusetts, Middle Aged, Multivariate Analysis, Principal Component Analysis, Prognosis, Proportional Hazards Models, Receptors, Tumor Necrosis Factor, Type II, Risk Assessment, Risk Factors, Time Factors
Show Abstract · Added April 15, 2014
OBJECTIVE - Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality.
APPROACH AND RESULTS - We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 ± 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD.
CONCLUSIONS - Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD.
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24 MeSH Terms
Prostaglandin E2 deficiency uncovers a dominant role for thromboxane A2 in house dust mite-induced allergic pulmonary inflammation.
Liu T, Laidlaw TM, Feng C, Xing W, Shen S, Milne GL, Boyce JA
(2012) Proc Natl Acad Sci U S A 109: 12692-7
MeSH Terms: Allergens, Animals, Antigens, Dermatophagoides, Asthma, Dinoprostone, Intercellular Adhesion Molecule-1, Intramolecular Oxidoreductases, Male, Mice, Mice, Knockout, Pneumonia, Prostaglandin-E Synthases, Pulmonary Eosinophilia, Receptors, Prostaglandin E, EP1 Subtype, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Thromboxane, Signal Transduction, Thromboxane A2, Up-Regulation
Show Abstract · Added March 26, 2014
Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.
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19 MeSH Terms
Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism.
Buehler PW, Baek JH, Lisk C, Connor I, Sullivan T, Kominsky D, Majka S, Stenmark KR, Nozik-Grayck E, Bonaventura J, Irwin DC
(2012) Am J Physiol Lung Cell Mol Physiol 303: L312-26
MeSH Terms: Animals, Blood Pressure, Blotting, Western, Cardiac Output, Cyclic N-Oxides, Hemodynamics, Hemoglobins, Humans, Hydrogen Peroxide, Inflammation, Infusion Pumps, Intercellular Adhesion Molecule-1, Kidney, Lipid Peroxidation, Lung, Lung Diseases, Male, Nitric Oxide, Oxidative Stress, Pulmonary Artery, Rats, Rats, Sprague-Dawley, Spin Labels, Vascular Diseases
Show Abstract · Added August 4, 2015
Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 μM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model.
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24 MeSH Terms
Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse model.
Chen JX, Zeng H, Reese J, Aschner JL, Meyrick B
(2012) Am J Physiol Heart Circ Physiol 302: H1003-12
MeSH Terms: Angiopoietin-2, Animals, Apoptosis, Caspase 3, Cells, Cultured, Coronary Vessels, Diabetes Mellitus, Disease Models, Animal, Endothelium, Vascular, Fibrosis, Intercellular Adhesion Molecule-1, Male, Mice, Mice, Mutant Strains, Myocardium, Neovascularization, Pathologic, Proto-Oncogene Proteins, Receptor, TIE-2, Up-Regulation, Vascular Cell Adhesion Molecule-1, Vascular Endothelial Growth Factor A, Wnt Proteins
Show Abstract · Added May 26, 2015
The angiopoietins/Tie-2 system is essential for the maintenance of vascular integrity and angiogenesis. The functional role of angiopoietin-2 (Ang-2) in the regulation of angiogenesis is dependent on other growth factors such as VEGF and a given physiopathological conditions. This study investigates the potential role of Ang-2 in myocardial angiogenesis and fibrosis formation in the diabetic db/db mouse. Diabetic db/db mice received intramyocardial administration of either adenovirus Ang-2 (Ad-CMV-Ang-2) or Ad-β-gal. The levels of Tie-2, VEGF, caspase-3, Wnt7b, fibroblast-specific protein-1 (FSP-1), and adhesion molecules (ICAM-1 and VCAM-1) expression were measured. Apoptosis, capillary density, and cardiac fibrosis were also analyzed in the db/db mouse hearts. Overexpression of Ang-2 suppressed Tie-2 and VEGF expression in db/db mouse hearts together with significant upregulation of Wnt7b expression. Overexpression of Ang-2 also sensitizes ICAM-1 and VCAM-1 expression in db/db mouse hearts. Immunohistochemical analysis revealed that overexpression of Ang-2 resulted in a gradual apoptosis as well as interstitial fibrosis formation, these leading to a significant loss of capillary density. Data from these studies were confirmed in cultured mouse heart microvascular endothelial cells (MHMEC) exposed to excessive Ang-2. Exposure of MHMEC to Ang-2 resulted in increased caspase-3 activity and endothelial apoptosis. Knockdown of Ang-2 attenuated high glucose-induced endothelial cell apoptosis. Further, counterbalance of Ang-2 by overexpression of Ang-1 reversed loss of capillary density and fibrosis formation in db/db mouse hearts. Our data demonstrate that Ang-2 increases endothelial apoptosis, sensitizes myocardial microvascular inflammation, and promotes cardiac fibrosis and thus contributes to loss of capillary density in diabetic diseases.
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22 MeSH Terms
Circulating soluble intercellular adhesion molecule 1 and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults Study.
Gross MD, Bielinski SJ, Suarez-Lopez JR, Reiner AP, Bailey K, Thyagarajan B, Carr JJ, Duprez DA, Jacobs DR
(2012) Clin Chem 58: 411-20
MeSH Terms: Adolescent, Adult, Atherosclerosis, Biomarkers, Calcinosis, Carotid Intima-Media Thickness, Carotid Stenosis, Coronary Artery Disease, Coronary Vessels, Female, Humans, Intercellular Adhesion Molecule-1, Male, Risk Assessment, Solubility, Young Adult
Show Abstract · Added February 15, 2014
BACKGROUND - Soluble intercellular adhesion molecule 1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
METHODS - sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification (CAC) through year 20 (n = 2378), and both carotid artery stenosis (n = 2432) and intima-media thickness (IMT) at year 20 (n = 2240).
RESULTS - Median sICAM-1 was 145.9 μg/L. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% CI 0.003-0.017 mm) higher per SD of sICAM-1 (44 μg/L) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol-lowering medication. With the same adjustment, the odds ratio (OR) for the presence of year-20 carotid artery stenosis per SD of sICAM-1 was 1.12 (95% CI 1.01-1.25, P < 0.04), whereas for occurrence of CAC progression the OR was 1.16 (1.04-1.31, P < 0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
CONCLUSIONS - sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades before the development of clinical CVD.
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16 MeSH Terms