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 RudelAnssi 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

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
TidskriftEuropean Heart Journal
Volym39
Utgåva27
Sidor (från-till)2562-2573
Antal sidor13
ISSN0195-668X
DOI
StatusPublicerad - 14 jul 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3121 Inre medicin

Citera det här

Ruuth, M., Nguyen, S. D., Vihervaara, T. M., Hilvo, M., Laajala, T. D., Kondadi, P. K., Gistera, A., Lähteenmäki, H., Kittilä, T., Huusko, J., Uusitupa, M., Schwab, U., Savolainen, M. J., Sinisalo, J., Lokki, M-L., Nieminen, M. S., Jula, A., Perola, M., Ylä-Herttula, S., ... 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, 39(27), 2562-2573. https://doi.org/10.1093/eurheartj/ehy319