Publications by authors named "Corey A Scipione"

13 Publications

  • Page 1 of 1

Role of myeloid-derived chemokine CCL5/RANTES at an early stage of atherosclerosis.

J Mol Cell Cardiol 2021 Mar 26;156:69-78. Epub 2021 Mar 26.

Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON M5S 1A8, Canada. Electronic address:

One of the hallmarks of atherosclerosis is ongoing accumulation of macrophages in the artery intima beginning at disease onset. Monocyte recruitment contributes to increasing macrophage abundance at early stages of atherosclerosis. Although the chemokine CCL5 (RANTES) has been studied in atherosclerosis, its role in the recruitment of monocytes to early lesions has not been elucidated. We show that expression of Ccl5 mRNA, as well as other ligands of the CCR5 receptor (Ccl3 and Ccl4), is induced in the aortic intima of Ldlr mice 3 weeks after the initiation of cholesterol-rich diet (CRD)-induced hypercholesterolemia. En face immunostaining revealed that CCL5 protein expression is also upregulated at 3 weeks of CRD. Blockade of CCR5 significantly reduced monocyte recruitment to 3-week lesions, suggesting that chemokine signaling through CCR5 is critical. However, we observed that Ccl5-deficiency had no effect on early lesion formation and CCL5-blockade did not affect monocyte recruitment in Ldlr mice. Immunostaining of the lesions in Ldlr mice and reciprocal bone marrow transplantation (BMT) of Ccl5 and Ccl5 mice revealed that CCL5 is expressed by both myeloid and endothelial cells. BMT experiments were carried out to determine if CCL5 produced by distinct cells has functions that may be concealed in Ccl5Ldlr mice. We found that hematopoietic cell-derived CCL5 regulates monocyte recruitment and the abundance of intimal macrophages in 3-week lesions of Ldlr mice but plays a minor role in 6-week lesions. Our findings suggest that there is a short window in early lesion formation during which myeloid cell-derived CCL5 has a critical role in monocyte recruitment and macrophage abundance.
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http://dx.doi.org/10.1016/j.yjmcc.2021.03.010DOI Listing
March 2021

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

Circ Res 2021 Feb 5;128(4):530-543. Epub 2021 Jan 5.

Toronto General Hospital Research Institute (J.I., C.A.S., S.J.H., M.G.A., J.A., S.A.D., T.E., J.M., N.I., H.M.I., C.K.P., X.G., K.T., J.J.-B., S.E., C.S.R., S.A.M., M.I.C.), University Health Network, Toronto, Canada.

Rationale: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT.

Objective: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms.

Methods And Results: mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of relative to mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT.

Conclusions: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316539DOI Listing
February 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

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

Circ Res 2020 Jul 16;127(3):402-426. Epub 2020 Jul 16.

La Jolla Institute for Immunology, CA (C.C.H., Y.G., H.Q.D., K.L.).

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371244PMC
July 2020

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

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

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

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

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

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

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve.

Circulation 2015 Aug 29;132(8):677-90. Epub 2015 Jul 29.

From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).

Background: Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve.

Methods And Results: We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD.

Conclusions: ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.016757DOI Listing
August 2015

Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor.

J Biol Chem 2015 May 16;290(18):11649-62. Epub 2015 Mar 16.

From the Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada,

Elevated levels of lipoprotein(a) (Lp(a)) have been identified as an independent risk factor for coronary heart disease. Plasma Lp(a) levels are reduced by monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the mechanism of Lp(a) catabolism in vivo and the role of PCSK9 in this process are unknown. We report that Lp(a) internalization by hepatic HepG2 cells and primary human fibroblasts was effectively reduced by PCSK9. Overexpression of the low density lipoprotein (LDL) receptor (LDLR) in HepG2 cells dramatically increased the internalization of Lp(a). Internalization of Lp(a) was markedly reduced following treatment of HepG2 cells with a function-blocking monoclonal antibody against the LDLR or the use of primary human fibroblasts from an individual with familial hypercholesterolemia; in both cases, Lp(a) internalization was not affected by PCSK9. Optimal Lp(a) internalization in both hepatic and primary human fibroblasts was dependent on the LDL rather than the apolipoprotein(a) component of Lp(a). Lp(a) internalization was also dependent on clathrin-coated pits, and Lp(a) was targeted for lysosomal and not proteasomal degradation. Our data provide strong evidence that the LDLR plays a role in Lp(a) catabolism and that this process can be modulated by PCSK9. These results provide a direct mechanism underlying the therapeutic potential of PCSK9 in effectively lowering Lp(a) levels.
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http://dx.doi.org/10.1074/jbc.M114.611988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416867PMC
May 2015