Publications by authors named "Marlys L Koschinsky"

86 Publications

Expert position statements: comparison of recommendations for the care of adults and youth with elevated lipoprotein(a).

Curr Opin Endocrinol Diabetes Obes 2021 04;28(2):159-173

The Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

Purpose Of Review: Summarize recent recommendations on clinical management of adults and youth with elevated lipoprotein(a) [Lp(a)] who are at-risk of or affected by cardiovascular disease (CVD).

Recent Findings: There is ample evidence to support elevated Lp(a) levels, present in approximately 20% of the general population, as a causal, independent risk factor for CVD and its role as a significant risk enhancer. Several guidelines and position statements have been published to assist in the identification, treatment and follow-up of adults with elevated levels of Lp(a). There is growing interest in Lp(a) screening and strategies to improve health behaviors starting in youth, although published recommendations for this population are limited. In addition to the well established increased risk of myocardial infarction, stroke and valvular aortic stenosis, data from the coronavirus pandemic suggest adults with elevated Lp(a) may have a particularly high-risk of cardiovascular complications. Lp(a)-specific-lowering therapies are currently in development. Despite their inability to lower Lp(a), use of statins have been shown to improve outcomes in primary and secondary prevention.

Summary: Considerable differences exist amongst published guidelines for adults on the use of Lp(a) in clinical practice, and recommendations for youth are limited. With increasing knowledge of Lp(a)'s role in CVD, including recent observations of COVID-19-related risk of cardiovascular complications, more harmonized and comprehensive guidelines for Lp(a) in clinical practice are required. This will facilitate clinical decision-making and help define best practices for identification and management of elevated Lp(a) in adults and youth.
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http://dx.doi.org/10.1097/MED.0000000000000624DOI Listing
April 2021

Development of an LC-MS/MS Proposed Candidate Reference Method for the Standardization of Analytical Methods to Measure Lipoprotein(a).

Clin Chem 2021 Mar;67(3):490-499

Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, USA.

Background: Use of lipoprotein(a) concentrations for identification of individuals at high risk of cardiovascular diseases is hampered by the size polymorphism of apolipoprotein(a), which strongly impacts immunochemical methods, resulting in discordant values. The availability of a reference method with accurate values expressed in SI units is essential for implementing a strategy for assay standardization.

Method: A targeted LC-MS/MS method for the quantification of apolipoprotein(a) was developed based on selected proteotypic peptides quantified by isotope dilution. To achieve accurate measurements, a reference material constituted of a human recombinant apolipoprotein(a) was used for calibration. Its concentration was assigned using an amino acid analysis reference method directly traceable to SI units through an unbroken traceability chain. Digestion time-course, repeatability, intermediate precision, parallelism, and comparability to the designated gold standard method for lipoprotein(a) quantification, a monoclonal antibody-based ELISA, were assessed.

Results: A digestion protocol providing comparable kinetics of digestion was established, robust quantification peptides were selected, and their stability was ascertained. Method intermediate imprecision was below 10% and linearity was validated in the 20-400 nmol/L range. Parallelism of responses and equivalency between the recombinant and endogenous apo(a) were established. Deming regression analysis comparing the results obtained by the LC-MS/MS method and those obtained by the gold standard ELISA yielded y = 0.98*ELISA +3.18 (n = 64).

Conclusions: Our method for the absolute quantification of lipoprotein(a) in plasma has the required attributes to be proposed as a candidate reference method with the potential to be used for the standardization of lipoprotein(a) assays.
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http://dx.doi.org/10.1093/clinchem/hvaa324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935757PMC
March 2021

Interaction of Autotaxin With Lipoprotein(a) in Patients With Calcific Aortic Valve Stenosis.

JACC Basic Transl Sci 2020 Sep 26;5(9):888-897. Epub 2020 Aug 26.

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada.

Our objectives were to determine whether autotaxin (ATX) is transported by lipoprotein(a) [Lp(a)] in human plasma and if could be used as a biomarker of calcific aortic valve stenosis (CAVS). We first found that ATX activity was higher in Lp(a) compared to low-density lipoprotein fractions in isolated fractions of 10 healthy participants. We developed a specific assay to measure ATX-Lp(a) in 88 patients with CAVS and 144 controls without CAVS. In a multivariable model corrected for CAVS risk factors, ATX-Lp(a) was associated with CAVS (p = 0.003). We concluded that ATX is preferentially transported by Lp(a) and might represent a novel biomarker for CAVS.
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http://dx.doi.org/10.1016/j.jacbts.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524777PMC
September 2020

Lipoprotein(a): Expanding our knowledge of aortic valve narrowing.

Trends Cardiovasc Med 2020 Jun 7. Epub 2020 Jun 7.

Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, Room 2260 Robarts Research Institute, 1151 Richmond Street North London, London N6A 5B7, ON, Canada.

Elevated levels of lipoprotein(a) [Lp(a)] have been identified as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and, more recently, calcific aortic valve disease (CAVD). CAVD is a slow, progressive disorder presenting as severe trileaflet calcification known as aortic valve stenosis (AS) that impairs valve motion and restricts ventricular outflow. AS afflicts 2% of the aging population (≥ 65 years) and tends to be quite advanced by the time it presents clinical symptoms of exertional angina, syncope, or heart failure. Currently, the only effective clinical therapy for AS patients is surgical or transcatheter aortic valve replacement. Evidence is accumulating that Lp(a) can exacerbate pathophysiological processes in CAVD, specifically, endothelial dysfunction, formation of foam cells, and promotion of a pro-inflammatory state. In the valve milieu, the pro-inflammatory effects of Lp(a) are manifested in valve thickening and mineralization through pro-osteogenic signaling and changes in gene expression in valve interstitial cells that is primarily facilitated by the oxidized phospholipid content of Lp(a). In AS pathogenesis, an incomplete understanding of the role of Lp(a) at the molecular level and the absence of appropriate animal models are barriers for the development of specific and effective clinical interventions designed to mitigate the role of Lp(a) in AS. However, the advent of effective therapies that dramatically lower Lp(a) provides the possibility of the first medical treatment to halt AS progression.
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http://dx.doi.org/10.1016/j.tcm.2020.06.001DOI Listing
June 2020

Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation.

Circ Res 2020 05 12;126(10):1346-1359. Epub 2020 Mar 12.

From the Experimental Vascular Medicine (J.G.S., L.A., J.C.B., M.V., A.K.G., J.K.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands.

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state.

Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.

Methods And Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.

Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208285PMC
May 2020

Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye?

Curr Opin Lipidol 2019 12;30(6):428-437

Department of Physiology & Pharmacology.

Purpose Of Review: Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue.

Recent Findings: Although the ability of PCSK9i to lower Lp(a) by 15-30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated.

Summary: Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.
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http://dx.doi.org/10.1097/MOL.0000000000000641DOI Listing
December 2019

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis.

J Lipid Res 2019 12 24;60(12):2082-2089. Epub 2019 Sep 24.

Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)] directed to apo(a) ( = 7) or placebo ( = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a) and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a) was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo ( < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% ( = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a) and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.
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http://dx.doi.org/10.1194/jlr.P094763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889713PMC
December 2019

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.

J Clin Lipidol 2019 May - Jun;13(3):374-392. Epub 2019 May 17.

Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.
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http://dx.doi.org/10.1016/j.jacl.2019.04.010DOI Listing
May 2020

Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis.

J Am Coll Cardiol 2019 05;73(17):2150-2162

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Background: Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.

Objectives: This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.

Methods: This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (V >2.0 m/s), who underwent baseline F-sodium fluoride (F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.

Results: Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.

Conclusions: In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.
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http://dx.doi.org/10.1016/j.jacc.2019.01.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494952PMC
May 2019

New Frontiers in Lp(a)-Targeted Therapies.

Trends Pharmacol Sci 2019 03 4;40(3):212-225. Epub 2019 Feb 4.

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada. Electronic address:

Interest in lipoprotein (a) [Lp(a)] has exploded over the past decade with the emergence of genetic and epidemiological studies pinpointing elevated levels of this unique lipoprotein as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). This review summarizes the most recent discoveries regarding therapeutic approaches to lower Lp(a) and presents these findings in the context of an emerging, although far from complete, understanding of the biosynthesis and catabolism of Lp(a). Application of Lp(a)-specific lowering agents to outcome trials will be the key to opening this new frontier in the battle against CVD.
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http://dx.doi.org/10.1016/j.tips.2019.01.004DOI Listing
March 2019

Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease.

Nat Rev Cardiol 2019 05;16(5):305-318

Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.
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http://dx.doi.org/10.1038/s41569-018-0153-2DOI Listing
May 2019

JCL roundtable-Lipoprotein(a): The emerging risk factor.

J Clin Lipidol 2018 Nov - Dec;12(6):1335-1345

Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address:

Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels.
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http://dx.doi.org/10.1016/j.jacl.2018.11.003DOI Listing
October 2019

Lipoprotein(a) and secondary prevention of atherothrombotic events: A critical appraisal.

J Clin Lipidol 2018 Nov - Dec;12(6):1358-1366. Epub 2018 Sep 11.

Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. Electronic address:

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are an independent, and possibly causal, risk factor for atherothrombotic diseases including coronary heart disease. The principal evidence base for this comes from large population studies focusing on first atherothrombotic events. However, inconsistent findings have been reported from studies investigating the impact of elevated Lp(a) on atherothrombotic events in subjects with preexisting cardiovascular disease. This question is very important because the secondary prevention population is recommended for Lp(a) screening by some guidelines and could be an important target group for Lp(a)-lowering therapies that are currently on the horizon. In this review, we survey the secondary prevention literature as it relates to Lp(a) and identify some possible confounding factors that may underlie the inconsistent findings, such as index event bias.
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http://dx.doi.org/10.1016/j.jacl.2018.08.012DOI Listing
October 2019

Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen on the surface of vascular endothelial and smooth muscle cells.

Thromb Res 2018 09 4;169:1-7. Epub 2018 Jul 4.

Department of Chemistry & Biochemistry, University of Windsor, Windsor, Ontario, Canada.

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein which has been identified as a causal risk factor for coronary heart disease and calcific aortic valve disease. Lp(a) consists of a low-density lipoprotein (LDL) moiety covalently linked to the unique glycoprotein apolipoprotein(a) [apo(a)]. Apo(a) is homologous to the fibrinolytic zymogen plasminogen and thus may interfere with plasminogen activation. Conversion of native Glu-plasminogen by plasmin to the more readily activatable Lys-plasminogen greatly accelerates plasminogen activation and is necessary for optimal stimulation of plasminogen activation on endothelial cells. Lp(a)/apo(a) has been previously shown to inhibit pericellular plasminogen activation on vascular cells, but the mechanism underling these observations is unknown. We therefore explored whether apo(a) can inhibit pericellular Glu- to Lys-plasminogen conversion on cell surfaces. A physiologically relevant recombinant version of apo(a) (17K) significantly inhibits plasmin-mediated Glu- to Lys-plasminogen conversion on human umbilical vein endothelial cells (HUVECs) and smooth muscle cells (SMCs). All isoforms of apo(a) that were analyzed, ranging in size from 3 to 21 kringle IV type 2 repeats, were able to inhibit conversion to a similar extent. Removal of the kringle V and protease domain of apo(a) strongly reduces the ability of apo(a) to inhibit conversion on HUVECs and SMCs. Removing the strong lysine binding site in KIV of apo(a) abolishes its ability to inhibit conversion on HUVECs and, to a lesser extent, on SMCs. These results indicate a novel mechanism in which apo(a) inhibits the positive feedback mechanism that accelerates plasmin formation on vascular cells.
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http://dx.doi.org/10.1016/j.thromres.2018.07.002DOI Listing
September 2018

Inhibition of pericellular plasminogen activation by apolipoprotein(a): Roles of urokinase plasminogen activator receptor and integrins αβ and αβ.

Atherosclerosis 2018 08 17;275:11-21. Epub 2018 May 17.

Department of Chemistry & Biochemistry, University of Windsor, Windsor, Ontario, N9B 3P4, Canada.

Background And Aims: Lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disorders including coronary heart disease and calcific aortic valve stenosis. Apolipoprotein(a) (apo(a)), the unique glycoprotein component of Lp(a), contains sequences homologous to plasminogen. Plasminogen activation is markedly accelerated in the presence of cell surface receptors and can be inhibited in this context by apo(a).

Methods: We evaluated the role of potential receptors in regulating plasminogen activation and the ability of apo(a) to mediate inhibition of plasminogen activation on vascular and monocytic/macrophage cells through knockdown (siRNA or blocking antibodies) or overexpression of various candidate receptors. Binding assays were conducted to determine apo(a) and plasminogen receptor interactions.

Results: The urokinase-type plasminogen activator receptor (uPAR) modulates plasminogen activation as well as plasminogen and apo(a) binding on human umbilical vein endothelial cells (HUVECs), human acute monocytic leukemia (THP-1) cells, and THP-1 macrophages as determined through uPAR knockdown and overexpression. Apo(a) variants lacking either the kringle V or the strong lysine binding site in kringle IV type 10 are not able to bind to uPAR to the same extent as wild-type apo(a). Plasminogen activation is also modulated, albeit to a lower extent, through the Mac-1 (αβ) integrin on HUVECs and THP-1 monocytes. Integrin αβ can regulate plasminogen activation on THP-1 monocytes and to a lesser extent on HUVECs.

Conclusions: These results indicate cell type-specific roles for uPAR, αβ, and αβ in promoting plasminogen activation and mediate the inhibitory effects of apo(a) in this process.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.05.029DOI Listing
August 2018

The journey towards understanding lipoprotein(a) and cardiovascular disease risk: are we there yet?

Curr Opin Lipidol 2018 06;29(3):259-267

Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.

Purpose Of Review: Evidence continues to mount for an important role for elevated plasma concentrations of lipoprotein(a) [Lp(a)] in mediating risk of atherothrombotic and calcific aortic valve diseases. However, there continues to be great uncertainty regarding some basic aspects of Lp(a) biology including its biosynthesis and catabolism, its mechanisms of action in health and disease, and the significance of its isoform size heterogeneity. Moreover, the precise utility of Lp(a) in the clinic remains undefined.

Recent Findings: The contribution of elevated Lp(a) to cardiovascular risk continues to be more precisely defined by larger studies. In particular, the emerging role of Lp(a) as a potent risk factor for calcific aortic valve disease has received much scrutiny. Mechanistic studies have identified commonalities underlying the impact of Lp(a) on atherosclerosis and aortic valve disease, most notably related to Lp(a)-associated oxidized phospholipids. The mechanisms governing Lp(a) concentrations remain a source of considerable dispute.

Summary: This article highlights some key remaining challenges in understanding Lp(a) actions and clinical significance. Most important in this regard is demonstration of a beneficial effect of lowering Lp(a), a development that is on the horizon as effective Lp(a)-lowering therapies are being tested in the clinic.
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http://dx.doi.org/10.1097/MOL.0000000000000499DOI Listing
June 2018

Therapeutic Lowering of Lipoprotein(a): A Role for Pharmacogenetics?

Circ Genom Precis Med 2018 02;11(2):e002052

From the Department of Biochemistry (M.B.B.) and Robarts Research Institute (M.L.K.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.

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http://dx.doi.org/10.1161/CIRCGEN.118.002052DOI Listing
February 2018

NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis.

J Am Coll Cardiol 2018 01;71(2):177-192

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.
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http://dx.doi.org/10.1016/j.jacc.2017.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868960PMC
January 2018

Lipoprotein(a) in clinical practice: New perspectives from basic and translational science.

Crit Rev Clin Lab Sci 2018 01 20;55(1):33-54. Epub 2017 Dec 20.

d Department of Biochemistry , Western University , London , Canada.

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). Genetic, epidemiological and in vitro data provide strong evidence for a pathogenic role for Lp(a) in the progression of atherothrombotic disease. Despite these advancements and a race to develop new Lp(a) lowering therapies, there are still many unanswered and emerging questions about the metabolism and pathophysiology of Lp(a). New studies have drawn attention to Lp(a) as a contributor to novel pathogenic processes, yet the mechanisms underlying the contribution of Lp(a) to CVD remain enigmatic. New therapeutics show promise in lowering plasma Lp(a) levels, although the complete mechanisms of Lp(a) lowering are not fully understood. Specific agents targeted to apolipoprotein(a) (apo(a)), namely antisense oligonucleotide therapy, demonstrate potential to decrease Lp(a) to levels below the 30-50 mg/dL (75-150 nmol/L) CVD risk threshold. This therapeutic approach should aid in assessing the benefit of lowering Lp(a) in a clinical setting.
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http://dx.doi.org/10.1080/10408363.2017.1415866DOI Listing
January 2018

Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach.

J Stroke Cerebrovasc Dis 2018 Mar 13;27(3):606-619. Epub 2017 Nov 13.

Stroke, Dementia and Heart Disease Laboratory, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Clinical Neurological Sciences at London Health Sciences Centre, Department of Epidemiology and Biostatistics, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address:

Background: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart.

Methods: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke.

Conclusions: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.038DOI Listing
March 2018

The renaissance of lipoprotein(a): Brave new world for preventive cardiology?

Prog Lipid Res 2017 10 6;68:57-82. Epub 2017 Sep 6.

School of Medicine, University of Western Australia, Perth, Australia; Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia. Electronic address:

Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran).
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http://dx.doi.org/10.1016/j.plipres.2017.09.001DOI Listing
October 2017

Pathobiology of Lp(a) in calcific aortic valve disease.

Expert Rev Cardiovasc Ther 2017 Oct 24;15(10):797-807. Epub 2017 Aug 24.

d Robarts Research Institute , London , ON , Canada.

Introduction: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder. Gene variant in the LPA gene, which encodes for apolipoprotein(a), has been associated at the genome-wide level with CAVD. The process whereby Lp(a) promotes the development of CAVD is under intensive investigation and recent data have shed important insights into disease biology. In this regard, autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes the mineralization of the aortic valve. Areas covered: In this paper, we are reviewing the biology of Lp(a) and the latest discoveries about the molecular processes that link this lipoprotein with the development of CAVD including the role of ATX. Expert commentary: Elevated Lp(a) levels are genetically determined and considered as an important risk factor for CAVD. Understanding how Lp(a) promotes the development/progression of CAVD is crucial as it may hold promise for the development of new therapies.
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http://dx.doi.org/10.1080/14779072.2017.1367286DOI Listing
October 2017

Plasminogen promotes cholesterol efflux by the ABCA1 pathway.

JCI Insight 2017 Aug 3;2(15). Epub 2017 Aug 3.

Department of Medicine, University of Washington, Seattle, Washington, USA.

Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.
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http://dx.doi.org/10.1172/jci.insight.92176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543924PMC
August 2017

Roles of the low density lipoprotein receptor and related receptors in inhibition of lipoprotein(a) internalization by proprotein convertase subtilisin/kexin type 9.

PLoS One 2017 27;12(7):e0180869. Epub 2017 Jul 27.

Robarts Research Institute and Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for cardiovascular disease. The mechanisms underlying Lp(a) clearance from plasma remain unclear, which is an obvious barrier to the development of therapies to specifically lower levels of this lipoprotein. Recently, it has been documented that monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) can lower plasma Lp(a) levels by 30%. Since PCSK9 acts primarily through the low density lipoprotein receptor (LDLR), this result is in conflict with the prevailing view that the LDLR does not participate in Lp(a) clearance. To support our recent findings in HepG2 cells that the LDLR can act as a bona fide receptor for Lp(a) whose effects are sensitive to PCSK9, we undertook a series of Lp(a) internalization experiments using different hepatic cells, with different variants of PCSK9, and with different members of the LDLR family. We found that PCSK9 decreased Lp(a) and/or apo(a) internalization by Huh7 human hepatoma cells and by primary mouse and human hepatocytes. Overexpression of human LDLR appeared to enhance apo(a)/Lp(a) internalization in both types of primary cells. Importantly, internalization of Lp(a) by LDLR-deficient mouse hepatocytes was not affected by PCSK9, but the effect of PCSK9 was restored upon overexpression of human LDLR. In HepG2 cells, Lp(a) internalization was decreased by gain-of-function mutants of PCSK9 more than by wild-type PCSK9, and a loss-of function variant had a reduced ability to influence Lp(a) internalization. Apo(a) internalization by HepG2 cells was not affected by apo(a) isoform size. Finally, we showed that very low density lipoprotein receptor (VLDLR), LDR-related protein (LRP)-8, and LRP-1 do not play a role in Lp(a) internalization or the effect of PCSK9 on Lp(a) internalization. Our findings are consistent with the idea that PCSK9 inhibits Lp(a) clearance through the LDLR, but do not exclude other effects of PCSK9 such as on Lp(a) biosynthesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180869PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531514PMC
October 2017

OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA-NF-κB pathway.

Cardiovasc Res 2017 Sep;113(11):1351-1363

Laboratory of Cardiovascular Pathobiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec/Quebec Heart and Lung Institute, Research Center, Department of Surgery, Laval University, 2725 Chemin Ste-Foy, Quebec, Quebec G1V-4G5, Canada.

Aims: Oxidatively modified lipoproteins may promote the development/progression of calcific aortic valve stenosis (CAVS). Oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA), a lipid mediator that accumulates in mineralized aortic valves. LPA activates at least six different G protein-coupled receptors, which may play a role in the pathophysiology of CAVS. We hypothesized that LPA derived from OxLDL may promote a NF-κB signature that drives osteogenesis in the aortic valve.

Methods And Results: The role of OxLDL-LPA was examined in isolated valve interstitial cells (VICs) and the molecular pathway was validated in human explanted aortic valves and in a mouse model of CAVS. We found that OxLDL-LPA promoted the mineralization and osteogenic transition of VICs through LPAR1 and the activation of a RhoA-NF-κB pathway. Specifically, we identified that RhoA/ROCK activated IκB kinase alpha, which promoted the phosphorylation of p65 on serine 536 (p65 pS536). p65 pS536 was recruited to the BMP2 promoter and directed an osteogenic program not responsive to the control exerted by the inhibitor of kappa B. In LDLR-/-/ApoB100/100/IGFII transgenic mice (IGFII), which develop CAVS under a high-fat and high-sucrose diet the administration of Ki16425, a Lpar1 blocker, reduced by three-fold the progression rate of CAVS and also decreased the osteogenic activity as measured with a near-infrared fluorescent probe that recognizes hydroxyapatite of calcium.

Conclusions: OxLDL-LPA promotes an osteogenic program in the aortic valve through a LPAR1-RhoA/ROCK-p65 pS536 pathway. LPAR1 may represent a suitable target to prevent the progression of CAVS.
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http://dx.doi.org/10.1093/cvr/cvx089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852522PMC
September 2017

Apolipoprotein(a) inhibits hepatitis C virus entry through interaction with infectious particles.

Hepatology 2017 06 28;65(6):1851-1864. Epub 2017 Apr 28.

EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.

The development of different cell culture models has greatly contributed to increased understanding of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. If overcome, this would open new perspectives to study HCV biology, including drug-resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient, and size-exclusion chromatography, we obtained from HCV-seronegative sera a purified fraction enriched in inhibitory factors. Mass spectrometric analysis identified apolipoprotein(a) (apo[a]) as a potential inhibitor of HCV entry. Apo(a) consists of 10 kringle IV domains (KIVs), one kringle V domain, and an inactive protease domain. The 10 KIVs are present in a single copy with the exception of KIV type 2 (KIV ), which is encoded in a variable number of tandemly repeated copies, giving rise to numerous apo(a) size isoforms. In addition, apo(a) covalently links to the apolipoprotein B component of a low-density lipoprotein through a disulfide bridge to form lipoprotein(a). Using a recombinant virus derived from the JFH1 strain, we confirmed that plasma-derived and recombinant lipoprotein(a) as well as purified recombinant apo(a) variants were able to specifically inhibit HCV by interacting with infectious particles. Our results also suggest that small isoforms are less inhibitory than the large ones. Finally, we observed that the lipoprotein moiety of HCV lipoviroparticles was essential for inhibition, whereas functional lysine-binding sites in KIV , KIV , and KIV were not required.

Conclusions: Our results identify apo(a) as an additional component of the lipid metabolism modulating HCV infection. (Hepatology 2017;65:1851-1864).
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http://dx.doi.org/10.1002/hep.29096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488163PMC
June 2017

Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans.

Circulation 2016 Aug 5;134(8):611-24. Epub 2016 Aug 5.

From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.).

Background: Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.

Methods: In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.

Results: We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).

Conclusions: These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.

Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study).
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.020838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995139PMC
August 2016

Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-κB pathway and SUMOylation.

J Cell Mol Med 2016 12 4;20(12):2249-2258. Epub 2016 Aug 4.

Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

The liver X receptor (LXR) is a cholesterol-sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti-inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin-8 (IL-8) secretion and nuclear factor-kappa B (NF-κB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)-induced IL-8 production in a dose-dependent manner without appreciable cytotoxicity. Western blotting and the NF-κB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL-8 promoter in LPC-stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin-like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL-8 induced by LPC. Furthermore, the LPC-induced degradation of inhibitory κBα was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO-specific protease Sentrin-specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC-mediated IL-8 expression. These findings indicate that LXR-mediated inflammatory gene repression correlates to the suppression of NF-κB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti-atherosclerotic role by attenuation of the NF-κB pathway in endothelial cells.
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http://dx.doi.org/10.1111/jcmm.12903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134410PMC
December 2016

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

J Lipid Res 2016 05 8;57(5):745-57. Epub 2015 Dec 8.

Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada Robarts Research Institute, Western University, London, ON, Canada

Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein.
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http://dx.doi.org/10.1194/jlr.R060582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847635PMC
May 2016

Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a).

J Lipid Res 2015 Dec 16;56(12):2273-85. Epub 2015 Oct 16.

Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada

Elevated lipoprotein (a) [Lp(a)] levels are a causal risk factor for coronary heart disease. Accumulating evidence suggests that Lp(a) can stimulate cellular inflammatory responses through the kringle-containing apolipoprotein (a) [apo(a)] component. Here, we report that recombinant apo(a) containing 17 kringle (17K) IV domains elicits a dose-dependent increase in interleukin (IL)-8 mRNA and protein expression in THP-1 and U937 macrophages. This effect was blunted by mutation of the lysine binding site in apo(a) kringle IV type 10, which resulted in the loss of oxidized phospholipid (oxPL) on apo(a). Trypsin-digested 17K had the same stimulatory effect on IL-8 expression as intact apo(a), while enzymatic removal of oxPL from apo(a) significantly blunted this effect. Using siRNA to assess candidate receptors, we found that CD36 and TLR2 may play roles in apo(a)-mediated IL-8 stimulation. Downstream of these receptors, inhibitors of MAPKs, Jun N-terminal kinase and ERK1/2, abolished the effect of apo(a) on IL-8 gene expression. To assess the roles of downstream transcription factors, luciferase reporter gene experiments were conducted using an IL-8 promoter fragment. The apo(a)-induced expression of this reporter construct was eliminated by mutation of IL-8 promoter binding sites for either NF-κB or AP-1. Our results provide a mechanistic link between oxPL modification of apo(a) and stimulation of proinflammatory intracellular signaling pathways.
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http://dx.doi.org/10.1194/jlr.M060210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655984PMC
December 2015