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

Maija Ruuth, Su Duy Nguyen, Terhi Marjut Vihervaara, Mika Hilvo, Teemu D. Laajala, Pradeep Kumar Kondadi, Anton Gistera, 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 & 12 muut Anssi Öörni, Marc Baumann, Amos Baruch, Reijo Laaksonen, Daniel F. J. Ketelhuth, Tero Aittokallio, Matti Jauhiainen, Reijo Käkelä, Jan Boren, Kevin Jon Williams, Petri T. Kovanen, Katariina Öörni

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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.
Alkuperäiskielienglanti
LehtiEuropean Heart Journal
Vuosikerta39
Numero27
Sivut2562-2573
Sivumäärä13
ISSN0195-668X
DOI - pysyväislinkit
TilaJulkaistu - 14 heinäkuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 3121 Sisätaudit
  • ATHEROSCLEROSIS
  • LDL
  • LDL Aggregation

Lainaa tätä

Ruuth, Maija ; Nguyen, Su Duy ; Vihervaara, Terhi Marjut ; Hilvo, Mika ; Laajala, Teemu D. ; Kondadi, Pradeep Kumar ; Gistera, Anton ; Lähteenmäki, Hanna ; Kittilä, Tiia ; Huusko, Jenni ; Uusitupa, Matti ; Schwab, Ursula ; Savolainen, Markku J. ; Sinisalo, Juha ; Lokki, Marja-Liisa ; Nieminen, Markku S. ; Jula, Antti ; Perola, Markus ; Ylä-Herttula, Seppo ; Rudel, Lawrence ; Öörni, Anssi ; Baumann, Marc ; Baruch, Amos ; Laaksonen, Reijo ; Ketelhuth, Daniel F. J. ; Aittokallio, Tero ; Jauhiainen, Matti ; Käkelä, Reijo ; Boren, Jan ; Williams, Kevin Jon ; Kovanen, Petri T. ; Öörni, Katariina. / Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Julkaisussa: European Heart Journal. 2018 ; Vuosikerta 39, Nro 27. Sivut 2562-2573.
@article{44b2e2e5ac93419c9a6183c4e7771ee7,
title = "Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths",
abstract = "AimsLow-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 resultsWe 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.ConclusionOur results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.",
keywords = "3121 Internal medicine, ATHEROSCLEROSIS, LDL, LDL Aggregation, Low-density lipoprotein, Atherosclerosis, Cardiovascular death, Sphingomyelin, Lipidomics, CORONARY-ARTERY-DISEASE, HEALTHY NORDIC DIET, SECRETORY SPHINGOMYELINASE, ATHEROGENIC LIPOPROTEINS, DEFICIENT MICE, ATHEROSCLEROSIS, RETENTION, PLASMA, CHOLESTEROL, INFLAMMATION",
author = "Maija Ruuth and Nguyen, {Su Duy} and Vihervaara, {Terhi Marjut} and Mika Hilvo and Laajala, {Teemu D.} and Kondadi, {Pradeep Kumar} and Anton Gistera and Hanna L{\"a}hteenm{\"a}ki and Tiia Kittil{\"a} and Jenni Huusko and Matti Uusitupa and Ursula Schwab and Savolainen, {Markku J.} and Juha Sinisalo and Marja-Liisa Lokki and Nieminen, {Markku S.} and Antti Jula and Markus Perola and Seppo Yl{\"a}-Herttula and Lawrence Rudel and Anssi {\"O}{\"o}rni and Marc Baumann and Amos Baruch and Reijo Laaksonen and Ketelhuth, {Daniel F. J.} and Tero Aittokallio and Matti Jauhiainen and Reijo K{\"a}kel{\"a} and Jan Boren and Williams, {Kevin Jon} and Kovanen, {Petri T.} and Katariina {\"O}{\"o}rni",
year = "2018",
month = "7",
day = "14",
doi = "10.1093/eurheartj/ehy319",
language = "English",
volume = "39",
pages = "2562--2573",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "27",

}

Ruuth, M, Nguyen, SD, Vihervaara, TM, Hilvo, M, Laajala, TD, Kondadi, PK, Gistera, A, Lähteenmäki, H, Kittilä, T, Huusko, J, Uusitupa, M, Schwab, U, Savolainen, MJ, Sinisalo, J, Lokki, M-L, Nieminen, MS, Jula, A, Perola, M, Ylä-Herttula, S, Rudel, L, Öörni, A, Baumann, M, Baruch, A, Laaksonen, R, Ketelhuth, DFJ, Aittokallio, T, Jauhiainen, M, Käkelä, R, Boren, J, Williams, KJ, Kovanen, PT & Öörni, K 2018, 'Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths', European Heart Journal, Vuosikerta 39, Nro 27, Sivut 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. / Ruuth, Maija; Nguyen, Su Duy; Vihervaara, Terhi Marjut; Hilvo, Mika; Laajala, Teemu D.; Kondadi, Pradeep Kumar; Gistera, Anton; Lähteenmäki, Hanna ; Kittilä, Tiia ; Huusko, Jenni; Uusitupa, Matti; Schwab, Ursula; Savolainen, Markku J.; Sinisalo, Juha; Lokki, Marja-Liisa; Nieminen, Markku S.; Jula, Antti; Perola, Markus; Ylä-Herttula, Seppo ; Rudel, Lawrence ; Öörni, Anssi; Baumann, Marc; Baruch, Amos; Laaksonen, Reijo; Ketelhuth, Daniel F. J.; Aittokallio, Tero ; Jauhiainen, Matti; Käkelä, Reijo ; Boren, Jan; Williams, Kevin Jon ; Kovanen, Petri T.; Öörni, Katariina.

julkaisussa: European Heart Journal, Vuosikerta 39, Nro 27, 14.07.2018, s. 2562-2573.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

AU - Ruuth, Maija

AU - Nguyen, Su Duy

AU - Vihervaara, Terhi Marjut

AU - Hilvo, Mika

AU - Laajala, Teemu D.

AU - Kondadi, Pradeep Kumar

AU - Gistera, Anton

AU - Lähteenmäki, Hanna

AU - Kittilä, Tiia

AU - Huusko, Jenni

AU - Uusitupa, Matti

AU - Schwab, Ursula

AU - Savolainen, Markku J.

AU - Sinisalo, Juha

AU - Lokki, Marja-Liisa

AU - Nieminen, Markku S.

AU - Jula, Antti

AU - Perola, Markus

AU - Ylä-Herttula, Seppo

AU - Rudel, Lawrence

AU - Öörni, Anssi

AU - Baumann, Marc

AU - Baruch, Amos

AU - Laaksonen, Reijo

AU - Ketelhuth, Daniel F. J.

AU - Aittokallio, Tero

AU - Jauhiainen, Matti

AU - Käkelä, Reijo

AU - Boren, Jan

AU - Williams, Kevin Jon

AU - Kovanen, Petri T.

AU - Öörni, Katariina

PY - 2018/7/14

Y1 - 2018/7/14

N2 - AimsLow-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 resultsWe 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.ConclusionOur results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

AB - AimsLow-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 resultsWe 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.ConclusionOur results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

KW - 3121 Internal medicine

KW - ATHEROSCLEROSIS

KW - LDL

KW - LDL Aggregation

KW - Low-density lipoprotein

KW - Atherosclerosis

KW - Cardiovascular death

KW - Sphingomyelin

KW - Lipidomics

KW - CORONARY-ARTERY-DISEASE

KW - HEALTHY NORDIC DIET

KW - SECRETORY SPHINGOMYELINASE

KW - ATHEROGENIC LIPOPROTEINS

KW - DEFICIENT MICE

KW - ATHEROSCLEROSIS

KW - RETENTION

KW - PLASMA

KW - CHOLESTEROL

KW - INFLAMMATION

U2 - 10.1093/eurheartj/ehy319

DO - 10.1093/eurheartj/ehy319

M3 - Article

VL - 39

SP - 2562

EP - 2573

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 27

ER -