Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths
Ruuth, Maija; Duy Nguyen, Su; Vihervaara, Terhi; Hilvo, Mika; Laajala, Teemu D; Kumar Kondadi, Pradeep; Gisterå, 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; Borén, Jan; Williams, Kevin Jon; Kovanen, Petri T; Öörni, Katariina (2018-07-04)
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
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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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