Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

Vaisar, Tomáš; Pennathur, Subramaniam; Green, Pattie S.; Gharib, Sina A.; Hoofnagle, Andrew N.; Cheung, Marian C.; Byun, Jaeman; Vuletic, Simona; Kassim, Sean Y.; Singh, Pragya; Chea, Helen; Knopp, Robert H.; Brunzell, John D.; Geary, Randolph L.; Chait, Alan; Zhao, Xue Qiao; Elkon, Keith B.; Marcovina, Santica; Ridker, Paul M.; Oram, John F.; Heinecke, Jay W.

doi:10.1172/jci26206

Cited by 863 publications

(943 citation statements)

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“…20 For these 58 genes, we retrieved from our meta‐analyses, association results for coding variants (missense, nonsense, and essential splice site) as well as variants annotated as eQTLs in the GTEx database 29. In total, we found 11 significant association signals from 6 different loci: missense variants for LIPG , APOA4 , and APOE , a nonsense variant for LPL , and eQTLs for LIPC and PLTP (Table 3).…”

Section: Resultsmentioning

confidence: 99%

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Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Low‐Kam

Rhainds

et al. 2018

JAHA

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BackgroundMacrophage cholesterol efflux to high‐density lipoproteins (HDLs) is the first step of reverse cholesterol transport. The cholesterol efflux capacity (CEC) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome‐wide association study approach, we aimed to identify pathways that regulate CEC in humans.Methods and ResultsWe measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome‐wide significant signals (P<6.25×10−9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology (CETP,LIPC,LPL,APOA1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE/C1/C2/C4 variant (rs141622900, P nonadjusted=1.0×10−11; P adjusted=8.8×10−9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP1CB/PLB1 and RBFOX3/ENPP7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome‐wide association study. These analyses identified 27 significant CEC associations, implicating 5 additional loci (GCKR,LIPG,PLTP,PPARA, and TRIB1).ConclusionsOur genome‐wide association study identified common genetic variation at the APOE/C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL‐based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.

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Section: Resultsmentioning

confidence: 99%

“…We also retrieved genes encoding for proteins found in HDL particles by proteomic analyses20; the list of these genes is presented in Table S3. For these 58 genes (literature review and/or proteomic analyses), we annotated and prioritized for secondary analyses missense, nonsense, and canonical splice site variants.…”

Section: Methodsmentioning

confidence: 99%

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Low‐Kam

Rhainds

et al. 2018

JAHA

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“…HDL protein profiling is increasingly being used to determine the biochemical composition of HDL (20,27,28). During acute systemic inflammation HDL becomes proinflammatory, loses its protective properties, and can even enhance atherogenesis (12,29).…”

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confidence: 99%

Improvement of lipid profile is accompanied by atheroprotective alterations in high‐density lipoprotein composition upon tumor necrosis factor blockade: A prospective cohort study in ankylosing spondylitis

Eijk¹,

Vries²,

Levels³

et al. 2009

Arthritis & Rheumatism

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Objective. Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS.Methods. In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ ionization time-of-flight analysis.Results. With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P ‫؍‬ 0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA.Conclusion. Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

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“…The protein composition of HDL in hypercholesterolemia, using shot-gun LC-MS/MS and probabilistic peptide scoring has been recently reported [128]. In order to test the hypothesis that lipoproteins can contain proteins with cardioprotective activities Vaisar et al [129] have used the same approach to analyze the composition of HDL isolated from healthy subjects and patients with CAD. Unexpectedly, multiple complement regulatory proteins and a variety of protease inhibitors were identified [129].…”

Section: Lipoprotein Proteomicsmentioning

confidence: 99%

“…In order to test the hypothesis that lipoproteins can contain proteins with cardioprotective activities Vaisar et al [129] have used the same approach to analyze the composition of HDL isolated from healthy subjects and patients with CAD. Unexpectedly, multiple complement regulatory proteins and a variety of protease inhibitors were identified [129]. These data support the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes.…”

Section: Lipoprotein Proteomicsmentioning

confidence: 99%

Vascular proteomics

Vivanco

Mas

Dardé

et al. 2007

Proteomics Clinical Apps

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The characterization of patients with acute coronary syndromes (ACS) at the molecular and cellular levels provides a novel vision for understanding the pathological and clinical expression of the disease. Recent advances in proteomic technologies permit the evaluation of systematic changes in protein expression in many biological systems and have been extensively applied to cardiovascular diseases (CVD). The cardiovascular system is in permanent intimate contact with blood, making blood-based biomarker discovery a particularly worthwhile approach. Thus, proteomics can potentially yield novel biomarkers reflecting CVD, establish earlier detection strategies, and monitor response to therapy. Here we review the different proteomic strategies used in the study of atherosclerosis and the novel proteins differentially expressed and secreted by atherosclerotic lesions which constitute novel potential biomarkers (HSP-27, Cathepsin D). Special attention is paid to MS-Imaging of atheroma plaque and the generation, for the first time, of 2-D images of lipids, showing the distribution of these molecules in the different areas of the atherosclerotic lesions. In addition new potential biomarkers have been identified in plasma (amyloid A1a, transtherytin), circulating cells (protein profile in monocytes from ACS patients) and individual cells constituents of atheroma plaques (endothelial, VSMC, macrophages) which provide novel insights into vascular pathophysiology.

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Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

Cited by 863 publications

References 68 publications

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Improvement of lipid profile is accompanied by atheroprotective alterations in high‐density lipoprotein composition upon tumor necrosis factor blockade: A prospective cohort study in ankylosing spondylitis

Vascular proteomics

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