University of Oulu

Maija Ruuth, Su Duy Nguyen, Terhi Vihervaara, Mika Hilvo, Teemu D Laajala, Pradeep Kumar Kondadi, Anton Gisterå, Hanna Lähteenmäki, Tiia Kittilä, Jenni Huusko, Matti Uusitupa, Ursula Schwab, Markku J Savolainen, Juha Sinisalo, Marja-Liisa Lokki, Markku S Nieminen, Antti Jula, Markus Perola, Seppo Ylä-Herttula, Lawrence Rudel, Anssi Öörni, Marc Baumann, Amos Baruch, Reijo Laaksonen, Daniel F J Ketelhuth, Tero Aittokallio, Matti Jauhiainen, Reijo Käkelä, Jan Borén, Kevin Jon Williams, Petri T Kovanen, Katariina Öörni; Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths, European Heart Journal, Volume 39, Issue 27, 14 July 2018, Pages 2562–2573, https://doi.org/10.1093/eurheartj/ehy319

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

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Author: Ruuth, Maija1,2; Duy Nguyen, Su1; Vihervaara, Terhi3;
Organizations: 1Atherosclerosis Research Laboratory, Wihuri Research Institute, Haartmaninkatu 8, 00290 Helsinki, Finland
2Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014 University of Helsinki, Finland
3Zora Biosciences, Biologinkuja 1, 02150 Espoo, Finland
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, P.O. Box 20, 00014 University of Helsinki, Finland
5Department of Mathematics and Statistics, University of Turku, Vesilinnantie 5, 20014 University of Turku, Finland
6Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SU Sahlgrenska, 41345 Gothenburg, Sweden
7Department of Medicine, Karolinska University Hospital, Karolinska Institute, Solna 171 76 Stockholm, Sweden
8Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211 Kuopio, Finland
9Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70211 Kuopio, Finland
10Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital, Puijonlaaksontie 2, P.O. Box 100, 70029 Kuopio, Finland
11Research Unit of Internal Medicine, University of Oulu, Pentti Kaiteran katu 1, P.O. Box 8000, 90014, Oulu, Finland
12Medical Research Center, Oulu University Hospital, Pentti Kaiteran katu 1, P.O. Box 8000, 90014 Oulu, Finland
13Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, P.O. Box 340, 00029 Helsinki, Finland
14Transplantation Laboratory, Medicum, University of Helsinki, Haartmaninkatu 3, P.O. Box 21, 00014 Helsinki, Finland
15Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare, Genomics and Biomarkers Unit, Mannerheimintie 166, P.O. Box 30, 00271 Helsinki, Finland
16Institute for Molecular Medicine Finland and Diabetes and Obesity Research Program, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014 University of Helsinki, Finland
17Heart Center and Gene Therapy Unit, Kuopio University Hospital, Puijonlaaksontie 2, P.O. Box 100, 70029 Kuopio, Finland
18Department of Biochemistry Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA
19Information Systems, Åbo Akademi University, Fänriksgatan 3A, 20500 Turku, Finland
20Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014 University of Helsinki, Finland
21Genentech Research and Early Development, 1 DNA Way Mailstop 258A, South San Francisco, CA 94080, USA
22Finnish Cardiovascular Research Center, University of Tampere, Kalevantie 4, 33100 Tampere, Finland
23Finnish Clinical Biobank Tampere, University Hospital of Tampere, Arvo Ylpön katu 6, 33520 Tampere, Finland
24Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland
25Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, P.O. Box 65, 00014 University of Helsinki, Finland
26Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE), Viikinkaari 1, P.O. Box 65, 00014 University of Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018091735945
Language: English
Published: Oxford University Press, 2018
Publish Date: 2018-09-17
Description:

Abstract

Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.

Methods and results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture.

Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

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Series: European heart journal
ISSN: 0195-668X
ISSN-E: 1522-9645
ISSN-L: 0195-668X
Volume: 39
Issue: 27
Pages: 2562 - 2573
DOI: 10.1093/eurheartj/ehy319
OADOI: https://oadoi.org/10.1093/eurheartj/ehy319
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 Internal medicine
Subjects:
Funding: Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation. This work was also supported by grants from the Finnish Foundation for Cardiovascular Research (to M.R., K.Ö.), from the Academy of Finland [265940 to K.Ö.] and [295504 to T.A.], from the Magnus Ehrnrooth Foundation (to K.Ö.), from Jane and Aatos Erkko Foundation (to M.J.), and from the Swedish Heart-Lung Foundation (to K.J.W.).
Copyright information: © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
  https://creativecommons.org/licenses/by-nc/4.0/