Yancey P.G.,Atherosclerosis Research Unit |
Blakemore J.,Atherosclerosis Research Unit |
Ding L.,Atherosclerosis Research Unit |
Fan D.,Atherosclerosis Research Unit |
And 4 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010
Objective: The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis. Method and results: LRP-1-/- macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1-/- cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1 macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1 vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1-/- phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1 -/- lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion: Macrophage LRP-1-/- deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1-/- macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation. © 2010 American Heart Association, Inc.
Baldassarre D.,University of Milan |
Baldassarre D.,Centro Cardiologico Monzino |
Veglia F.,Centro Cardiologico Monzino |
Hamsten A.,Atherosclerosis Research Unit |
And 12 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013
Objective-To investigate whether several different measures of carotid intima-media thickness (IMT) progression are associated with subsequent vascular events and whether such associations are independent of baseline carotid atherosclerotic profile and Framingham risk factors. Approach and Results-A longitudinal cohort study (the Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population study) was performed in 7 centers in 5 European countries (Finland, France, Italy, the Netherlands, and Sweden). Three thousand four hundred eighty-two subjects (median age 64.1 years; 47.8% men) with ≥3 vascular risk factors were recruited and monitored for a postprogression median follow-up of 21.5 months, during which time 129 subjects experienced a first vascular event (incidence of 20.4 per 1000 person-years). The 15th month progression of mean and maximum carotid IMT of the left and right common carotids, bifurcations, internal carotid arteries, and their composite measures, as well as the fastest IMTmax progression (Fastest-IMTmax-progr) detected in the whole carotid tree regardless of location, were used in statistical analyses. All carotid IMT measures showed significant progression during the first 15 months (P<0.001), but only the Fastest-IMTmax-progr was significantly associated with the risk of subsequent vascular events. The Fastest-IMTmax-progr association persisted after Bonferroni correction for multiple comparisons and after adjustments for Framingham risk factors and pharmacological treatments (all P<0.005). The use of Framingham Risk Score in place of Framingham risk factors provided almost identical results (P=0.003). CONCLUSIONS-The Fastest-IMTmax-progr, a novel approach to assess carotid IMT progression, identifies focal increases of carotid IMT and, in contrast to other progression variables, is associated with cardiovascular risk. © 2013 American Heart Association, Inc.
Mishra V.K.,Atherosclerosis Research Unit |
Palgunachari M.N.,Atherosclerosis Research Unit |
McPherson D.T.,Center for Research |
Anantharamaiah G.M.,Atherosclerosis Research Unit |
Anantharamaiah G.M.,Comprehensive Cancer Center
Biochemical and Biophysical Research Communications | Year: 2013
High density lipoprotein (HDL) associated paraoxonase-1 (PON1) is crucial for the anti-oxidant, anti-inflammatory, and anti-atherogenic properties of HDL. Discoidal apolipoprotein (apo)A-I:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) complex has been shown to be the most effective in binding PON1, stabilizing it, and enhancing its lactonase and inhibitory activity of low density lipoprotein oxidation. Based on our earlier study demonstrating that apoA-I mimetic peptide 4F forms discoidal complex with 1,2-dimyristoyl-sn-glycero-3-phosphocholine, we hypothesized that lipid complexes of 4F would be able to bind PON1 and enhance its activity and stability. To test our hypothesis, we have expressed and purified a recombinant PON1 (rPON1) and studied its interaction with 4F:POPC complex. Our studies show significant increase, compared to the control, in the paraoxonase activity and stability of rPON1 in the presence of 4F:POPC complex. We propose that 4F:POPC complex is a novel platform for PON1 binding, increasing its stability, and enhancing its enzyme activity. We propose a structural model for the 4F:POPC:PON1 ternary complex that is consistent with our results and published observations. © 2012 Elsevier Inc.
Polyzos K.A.,Alfa Institute of Biomedical science AIBS |
Polyzos K.A.,Atherosclerosis Research Unit |
Konstantelias A.A.,Alfa Institute of Biomedical science AIBS |
Falagas M.E.,Alfa Institute of Biomedical science AIBS |
And 2 more authors.
Europace | Year: 2015
Infectious complications after cardiac implantable electronic device (CIED) implantation are increasing over time and are associated with substantial mortality and healthcare costs. The aim of this study was to systematically summarize the literature on risk factors for infection after pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantation. Electronic searches (up to January 2014) were performed in PubMed, Scopus, and Web of Science databases. Sixty studies (21 prospective, 9 case-control, and 30 retrospective cohort studies) met the inclusion criteria. The average device infection rate was 1-1.3%. In the meta-analysis, significant host-related risk factors for infection included diabetes mellitus (odds ratio (OR) [95% confidence interval] = 2.08 [1.62-2.67]), end-stage renal disease (OR = 8.73 [3.42-22.31]), chronic obstructive pulmonary disease (OR = 2.95 [1.78-4.90]), corticosteroid use (OR = 3.44 [1.62-7.32]), history of the previous device infection (OR = 7.84 [1.94-31.60]), renal insufficiency (OR = 3.02 [1.38-6.64]), malignancy (OR = 2.23 [1.26-3.95]), heart failure (OR = 1.65 [1.14-2.39]), pre-procedural fever (OR = 4.27 [1.13-16.12]), anticoagulant drug use (OR = 1.59 [1.01-2.48]), and skin disorders (OR = 2.46 [1.04-5.80]). Regarding procedure-related factors, post-operative haematoma (OR = 8.46 [4.01-17.86]), reintervention for lead dislodgement (OR = 6.37 [2.93-13.82]), device replacement/revision (OR = 1.98 [1.46-2.70]), lack of antibiotic prophylaxis (OR = 0.32 [0.18-0.55]), temporary pacing (OR = 2.31 [1.36-3.92]), inexperienced operator (OR = 2.85 [1.23-6.58]), and procedure duration (weighted mean difference = 9.89 [0.52-19.25]) were all predictors of CIED infection. Among device-related characteristics, abdominal pocket (OR = 4.01 [2.48-6.49]), epicardial leads (OR = 8.09 [3.46-18.92]), positioning of two or more leads (OR = 2.02 [1.11-3.69]), and dual-chamber systems (OR = 1.45 [1.02-2.05]) predisposed to device infection. This systematic review on risk factors for CIED infection may contribute to developing better infection control strategies for high-risk patients and can also help risk assessment in the management of device revisions. © The Author 2015.
Datta G.,Atherosclerosis Research Unit |
White C.R.,University of Alabama at Birmingham |
Dashti N.,Atherosclerosis Research Unit |
Chaddha M.,Atherosclerosis Research Unit |
And 6 more authors.
Atherosclerosis | Year: 2010
Apolipoprotein E (apoE) exerts prominent anti-inflammatory effects and undergoes recycling by target cells. We previously reported that the peptide Ac-hE18A-NH2, composed of the receptor binding domain (LRKLRKRLLR) of apoE covalently linked to the Class A amphipathic peptide 18A, dramatically lowers plasma cholesterol and lipid hydroperoxides and enhances paraoxonase activity in dyslipidemic animal models. The objective of this study was to determine whether this peptide, analogous to apoE, exerts anti-inflammatory effects and undergoes recycling under in vitro conditions. Pulse chase studies using [125I]-Ac-hE18A-NH2 in THP-1 derived macrophages and HepG2 cells showed greater amounts of intact peptide in the cells at later time points indicating recycling of the peptide. Ac-hE18A-NH2 induced a 2.5-fold increase in preβ-HDL in the conditioned media of HepG2 cells. This effect persisted for 3 days after removal of the peptide from culture medium. Ac-hE18A-NH2 also induced the secretion of cell surface apoE from THP-1 macrophages. In addition, the peptide increased cholesterol efflux from THP-1 cells by an ABCA1 independent mechanism. Moreover, Ac-hE18A-NH2 inhibited LPS-induced vascular cell adhesion molecule-1 (VCAM-1) expression, and reduced monocyte adhesion in human umbilical vein endothelial cells (HUVECs). It also reduced the secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from THP-1 macrophages even when administered post-LPS and abolished the 18-fold increase in LPS-induced mRNA levels for MCP-1 in THP-1 cells. Taken together, these results suggest that addition of the putative apoE receptor-domain to the Class A amphipathic peptide 18A results in a peptide that, similar to apoE, recycles, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-inflammatory effects. Such a peptide has great potential as a therapeutic agent in the management of atherosclerosis and other inflammatory diseases. © 2009 Elsevier Ireland Ltd. All rights reserved.
Navab M.,University of California at Los Angeles |
Navab M.,Atherosclerosis Research Unit |
Reddy S.T.,Atherosclerosis Research Unit |
Reddy S.T.,University of California at Los Angeles |
And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012
Oxidized phospholipids are found in the vasculature of animal models of atherosclerosis, in human atherosclerotic lesions, and in other inflammatory diseases. Oxidized phospholipids cause vascular and nonvascular cells to initiate an inflammatory reaction. Metabolites of arachidonic acid, such as 12-hydroxyeicosatetraenoic acid, can mimic some of the inflammatory properties of oxidized phospholipids. In vitro and in vivo normal high-density lipoprotein (HDL), normal apolipoprotein A-I, and apolipoprotein A-I mimetic peptides, each likely acting in a different manner, prevent the inflammatory reaction characteristic of atherosclerosis, and this is associated with decreased levels of oxidized lipids in tissues and cells. HDL from animal models of atherosclerosis or from humans with atherosclerosis or from humans or animals with other chronic inflammatory diseases does not prevent the inflammatory reaction characteristic of atherosclerosis and may even enhance the inflammatory reaction. In mice and perhaps humans,.30% of the steady-state plasma HDL-cholesterol pool is derived from the small intestine. The metabolism of phospholipids by gut bacteria has been recently implicated in atherosclerosis in both mice and humans. Studies with apolipoprotein A-I mimetic peptides suggest that the small intestine is a major tissue regulating systemic inflammation in mouse models of atherosclerosis and may be important for determining the functionality of HDL. © 2012 American Heart Association, Inc.
Farias-Eisner G.,Atherosclerosis Research Unit |
Su F.,University of California at Los Angeles |
Robbins T.,Pathway Diagnostics Inc |
Kotlerman J.,University of California at Los Angeles |
And 3 more authors.
American Journal of Obstetrics and Gynecology | Year: 2010
Objective: The objective of this study was to determine the efficacy of 3 previously described ovarian cancer serum biomarkers (apolipoprotein-1 [ApoA-I], prealbumin [TTR], transferrin [TF]) in the detection of endometrioid and papillary serous adenocarcinoma of the endometrium. Study Design: ApoA-I, TTR, and TF levels were measured in serum samples that were obtained from 433 individuals that included 90 women with normal endometrium, 210 women with early-stage endometrial cancer, and 133 women with late-stage endometrial cancer. Multivariate regression models were constructed to evaluate the usefulness of the biomarkers in the detection of endometrial cancer. Results: ApoA-I, TTR, and TF distinguished normal samples from early-stage endometrial cancer with a sensitivity of 71% (specificity, 88%) and normal samples from late stage endometrial cancer with a sensitivity of 82% (specificity, 86%). Conclusion: The biomarker panel that consists of ApoA-I, TTR, and TF may prove to be a useful clinical tool for the detection of endometrial cancer. © 2010 Mosby, Inc. All rights reserved.
Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C high monocytosis: Evidence that the effects are not apolipoprotein e dependent
Yancey P.G.,Atherosclerosis Research Unit |
Ding Y.,Atherosclerosis Research Unit |
Ding Y.,Jilin University |
Fan D.,Atherosclerosis Research Unit |
And 8 more authors.
Circulation | Year: 2011
Bacground-: We previously demonstrated that macrophage low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) deficiency increases atherosclerosis despite antiatherogenic changes including decreased uptake of remnants and increased secretion of apolipoprotein E (apoE). Thus, our objective was to determine whether the atheroprotective effects of LRP1 require interaction with apoE, one of its ligands with multiple beneficial effects. Methods and Result-: We examined atherosclerosis development in mice with specific deletion of macrophage LRP1 (apoE-/- MΦLRP1) and in LDLR-/- mice reconstituted with apoE MΦLRP1-/- bone marrow. The combined absence of apoE and LRP1 promoted atherogenesis more than did macrophage apoE deletion alone in both apoE-producing LDLR-/- mice (+88%) and apoE-/- mice (+163%). The lesions of both mouse models with apoE-/- LRP1-/- macrophages had increased macrophage content. In vitro, apoE-/- and LRP1-/- additively inhibit macrophage apoptosis. Furthermore, there was excessive accumulation of apoptotic cells in lesions of both LDLR mice (+110%) and apoE MΦLRP1-/- mice (+252%). The apoptotic cell accumulation was partially due to decreased efferocytosis as the ratio of free to cell-associated apoptotic nuclei was 3.5-fold higher in lesions of apoE MΦLRP1 -/- versus apoE mice. Lesion necrosis was also increased (6 fold) in apoE MΦLRP1-/- versus apoE mice. Compared with apoE mice, the spleens of apoE MΦLRP1-/- mice contained 1.6- and 2.4-fold more total and Ly6-C monocytes. Finally, there were 3.6- and 2.4-fold increases in Ly6-Chigh and CC-chemokine receptor 2-positive cells in lesions of apoE MΦLRP1-/- versus apoE mice, suggesting that accumulation of apoptotic cells enhances lesion development and macrophage content by promoting the recruitment of inflammatory monocytes. Conclusion-: Low-density lipoprotein receptor protein 1 exerts antiatherogenic effects via pathways independent of apoE-/- involving macrophage apoptosis and monocyte recruitment. © 2011 American Heart Association, Inc.
Tavori H.,Atherosclerosis Research Unit |
Fan D.,University of South Carolina |
Blakemore J.L.,Atherosclerosis Research Unit |
Yancey P.G.,Atherosclerosis Research Unit |
And 5 more authors.
Circulation | Year: 2013
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation. Methods and Results: To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR-/- mice, in which murine PCSK9 levels were already 10-fold higher than in wildtype mice. In addition, LDLR+/- mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR-/- recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression. Conclusions: Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels. © 2013 American Heart Association, Inc.
Petri M.H.,Karolinska University Hospital |
Laguna-Fernandez A.,Karolinska University Hospital |
Gonzalez-Diez M.,Atherosclerosis Research Unit |
Paulsson-Berne G.,Karolinska University Hospital |
And 2 more authors.
Cardiovascular Research | Year: 2015
Aims The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ ALX signalling in atherosclerosis. Methods and results Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations,we generated Ldlr-/-xFpr2-/- mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr-/-xFpr2+/+ mice. These findings were reproduced by transplantation of Fpr2-/- bone marrowinto Ldlr-/- mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2-/- macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr-/-xFpr2-/- mice exhibited decreased collagen content, and Fpr2-/- SMCs exhibited a profile of increased collagenase and decreased collagen production pathways. Conclusion FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability. © The Author 2014.