A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, ismodifiable, and associates with future cardiovascular deaths
Tekijät: Ruuth M, Nguyen SD, Vihervaara T, Hilvo M, Laajala TD, Kondadi PK, Gistera A, Lahteenmaki H, Kittila T, Huusko J, Uusitupa M, Schwab U, Savolainen MJ, Sinisalo J, Lokki ML, Nieminen MS, Jula A, Perola M, Yla-Herttula S, Rudel L, Oorni A, Baumann M, Baruch A, Laaksonen R, Ketelhuth DFJ, Aittokallio T, Jauhiainen M, Kakela R, Boren J, Williams KJ, Kovanen PT, Oorni K
Kustantaja: OXFORD UNIV PRESS
Julkaisuvuosi: 2018
Journal: European Heart Journal
Tietokannassa oleva lehden nimi: EUROPEAN HEART JOURNAL
Lehden akronyymi: EUR HEART J
Vuosikerta: 39
Numero: 27
Aloitussivu: 2562
Lopetussivu: 2573
Sivujen määrä: 13
ISSN: 0195-668X
eISSN: 1522-9645
DOI: https://doi.org/10.1093/eurheartj/ehy319
Verkko-osoite: https://academic.oup.com/eurheartj/article/39/27/2562/5049093
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/32841565
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
