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Journal ArticleDOI

HDL in Immune-Inflammatory Responses: Implications beyond Cardiovascular Diseases.

29 Apr 2021-Cells (Multidisciplinary Digital Publishing Institute)-Vol. 10, Iss: 5, pp 1061
TL;DR: In this article, HDL-C levels and HDL composition are altered in patients with autoimmune diseases and usually associated with disease severity, and the contribution of HDL beyond cholesterol efflux is elucidated.
Abstract: High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.
Citations
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Journal ArticleDOI
TL;DR: In this paper , a U-shaped relationship between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality.
Abstract: Graphical Abstract Graphical Abstract The great complexity of HDL. High-density lipoprotein (HDL) particles carry a large number of proteins and lipids, which contribute to define their compositional and functional complexity. HDLs exert multiple protective activities, essentially by three major mechanisms. HDLs, however, can lose their protective functions and even gain adverse functions in chronic diseases or during infections. U-shaped relationships between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality. LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PONI, paraoxonase 1; S1P, sphingosine-1-phosphate; ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; SAA, serum amyloid A; OxPL, oxidized phospholipids

18 citations

Journal ArticleDOI
TL;DR: A review of HDL cholesterol immunomodulation in the context of the mechanisms of chronic inflammation and immunosuppression causing persistent inflammation and catabolism syndrome (PICS) is presented in this paper.
Abstract: Purpose of review This study reviews the mechanisms of HDL cholesterol immunomodulation in the context of the mechanisms of chronic inflammation and immunosuppression causing persistent inflammation, immunosuppression and catabolism syndrome (PICS) and describes potential therapies and gaps in current research. Recent findings Low HDL cholesterol is predictive of acute sepsis severity and outcome. Recent research has indicated apolipoprotein is a prognostic indicator of long-term outcomes. The pathobiologic mechanisms of PICS have been elucidated in the past several years. Recent research of the interaction of HDL pathways in related chronic inflammatory diseases may provide insights into further mechanisms and therapeutic targets. Summary HDL significantly influences innate and adaptive immune pathways relating to chronic disease and inflammation. Further research is needed to better characterize these interactions in the setting of PICS.

9 citations

Journal ArticleDOI
TL;DR: In this article , the apoM-sphingosine-1-phosphate complex was found to be critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced β-cell survival and inhibition of hepatic glucose production.
Abstract: To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM).In young T1DM patients with early renal impairment and a high inflammatory score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic β-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced β-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions.Extensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.

9 citations

Journal ArticleDOI
TL;DR: A current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL is provided and possible therapeutic implications and options are discussed.
Abstract: Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.

7 citations

Journal ArticleDOI
TL;DR: A review of the evidence on modifications of major lipid and lipoprotein components, including LDL, HDL, TG, apolipoprotein, and Lipoprotein(a), is presented in this paper.
Abstract: Despite advances in pharmacotherapy, intervention devices and techniques, residual cardiovascular risks still cause a large burden on public health. Whilst most guidelines encourage achieving target levels of specific lipids and lipoproteins to reduce these risks, increasing evidence has shown that molecular modification of these lipoproteins also has a critical impact on their atherogenicity. Modification of low-density lipoprotein (LDL) by oxidation, glycation, peroxidation, apolipoprotein C-III adhesion, and the small dense subtype largely augment its atherogenicity. Post-translational modification by oxidation, carbamylation, glycation, and imbalance of molecular components can reduce the capacity of high-density lipoprotein (HDL) for reverse cholesterol transport. Elevated levels of triglycerides (TGs), apolipoprotein C-III and lipoprotein(a), and a decreased level of apolipoprotein A-I are closely associated with atherosclerotic cardiovascular disease. Pharmacotherapies aimed at reducing TGs, lipoprotein(a), and apolipoprotein C-III, and enhancing apolipoprotein A-1 are undergoing trials, and promising preliminary results have been reported. In this review, we aim to update the evidence on modifications of major lipid and lipoprotein components, including LDL, HDL, TG, apolipoprotein, and lipoprotein(a). We also discuss examples of translating findings from basic research to potential therapeutic targets for drug development.

7 citations

References
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Journal ArticleDOI
TL;DR: Although there was evidence of an off-target effect of torcetrapib, it cannot rule out adverse effects related to CETP inhibition, and the trial was terminated prematurely because of an increased risk of death and cardiac events.
Abstract: Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both compari...

2,832 citations

Journal ArticleDOI
11 Nov 2009-JAMA
TL;DR: Lid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
Abstract: CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. RESULTS: The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. CONCLUSION: Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.

2,196 citations

Journal ArticleDOI
Benjamin F. Voight1, Benjamin F. Voight2, Benjamin F. Voight3, Gina M. Peloso4, Gina M. Peloso5, Marju Orho-Melander6, Ruth Frikke-Schmidt7, Maja Barbalić8, Majken K. Jensen3, George Hindy6, Hilma Holm9, Eric L. Ding3, Toby Johnson10, Heribert Schunkert11, Nilesh J. Samani12, Nilesh J. Samani13, Robert Clarke14, Jemma C. Hopewell14, John F. Thompson12, Mingyao Li1, Gudmar Thorleifsson9, Christopher Newton-Cheh, Kiran Musunuru2, Kiran Musunuru3, James P. Pirruccello3, James P. Pirruccello2, Danish Saleheen15, Li Chen16, Alexandre F.R. Stewart16, Arne Schillert11, Unnur Thorsteinsdottir17, Unnur Thorsteinsdottir9, Gudmundur Thorgeirsson17, Sonia S. Anand18, James C. Engert19, Thomas M. Morgan20, John A. Spertus21, Monika Stoll22, Klaus Berger22, Nicola Martinelli23, Domenico Girelli23, Pascal P. McKeown24, Christopher Patterson24, Stephen E. Epstein25, Joseph M. Devaney25, Mary Susan Burnett25, Vincent Mooser26, Samuli Ripatti27, Ida Surakka27, Markku S. Nieminen27, Juha Sinisalo27, Marja-Liisa Lokki27, Markus Perola4, Aki S. Havulinna4, Ulf de Faire28, Bruna Gigante28, Erik Ingelsson28, Tanja Zeller29, Philipp S. Wild29, Paul I.W. de Bakker, Olaf H. Klungel30, Anke-Hilse Maitland-van der Zee30, Bas J M Peters30, Anthonius de Boer30, Diederick E. Grobbee30, Pieter Willem Kamphuisen31, Vera H.M. Deneer, Clara C. Elbers30, N. Charlotte Onland-Moret30, Marten H. Hofker31, Cisca Wijmenga31, W. M. Monique Verschuren, Jolanda M. A. Boer, Yvonne T. van der Schouw30, Asif Rasheed, Philippe M. Frossard, Serkalem Demissie5, Serkalem Demissie4, Cristen J. Willer32, Ron Do3, Jose M. Ordovas33, Jose M. Ordovas34, Gonçalo R. Abecasis32, Michael Boehnke32, Karen L. Mohlke35, Mark J. Daly3, Mark J. Daly2, Candace Guiducci2, Noël P. Burtt2, Aarti Surti2, Elena Gonzalez2, Shaun Purcell3, Shaun Purcell2, Stacey Gabriel2, Jaume Marrugat, John F. Peden14, Jeanette Erdmann11, Patrick Diemert11, Christina Willenborg11, Inke R. König11, Marcus Fischer36, Christian Hengstenberg36, Andreas Ziegler11, Ian Buysschaert37, Diether Lambrechts37, Frans Van de Werf37, Keith A.A. Fox38, Nour Eddine El Mokhtari39, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber39, Arne Schäfer39, John Danesh15, Stefan Blankenberg29, Robert Roberts16, Ruth McPherson16, Hugh Watkins14, Alistair S. Hall40, Kim Overvad41, Eric B. Rimm3, Eric Boerwinkle8, Anne Tybjærg-Hansen7, L. Adrienne Cupples5, L. Adrienne Cupples4, Muredach P. Reilly1, Olle Melander6, Pier Mannuccio Mannucci42, Diego Ardissino, David S. Siscovick43, Roberto Elosua, Kari Stefansson9, Kari Stefansson17, Christopher J. O'Donnell4, Christopher J. O'Donnell3, Veikko Salomaa4, Daniel J. Rader1, Leena Peltonen27, Leena Peltonen44, Stephen M. Schwartz43, David Altshuler, Sekar Kathiresan 
11 Aug 2012
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10

1,878 citations

Journal ArticleDOI
05 Nov 2003-JAMA
TL;DR: A recombinant ApoA-I Milano/phospholipid complex administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS, and results require confirmation in larger clinical trials with morbidity and mortality end points.
Abstract: ContextAlthough low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano–phospholipid complexes produces rapid regression of atherosclerosis in animal models.ObjectiveWe assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS).DesignThe study was a double-blind, randomized, placebo-controlled multicenter pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS).SettingTen community and tertiary care hospitals in the United States.PatientsBetween November 2001 and March 2003, 123 patients aged 38 to 82 years consented, 57 were randomly assigned, and 47 completed the protocol.InterventionsIn a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments.Main Outcome MeasuresThe primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness.ResultsThe mean (SD) percent atheroma volume decreased by −1.06% (3.17%) in the combined ETC-216 group (median, −0.81%; 95% confidence interval [CI], −1.53% to −0.34%; P = .02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%; median, 0.03%; 95% CI, −1.11% to 1.43%; P = .97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was −14.1 mm3 or a 4.2% decrease from baseline (P<.001).ConclusionsA recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.

1,745 citations

Journal ArticleDOI
TL;DR: In this paper, HDL has been shown to have anti-atherogenic properties, which may explain the ability of HDL to promote the efflux of cholesterol from cells in the artery wall.
Abstract: There are several well-documented functions of high-density lipoprotein (HDL) that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDL to promote the efflux of cholesterol from cells. This process may minimize the accumulation of foam cells in the artery wall. However, HDL has additional properties that may also be antiatherogenic. For example, HDL is an effective antioxidants. The major proteins of HDL, apoA-I and apoA-II, as well as other proteins such as paraoxonase that cotransport with HDL in plasma, are well-known to have antioxidant properties. As a consequence, HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis.

1,241 citations