LDL (low-density lipoprotein) is a particle that carries cholesterol in the blood. High levels of LDL-cholesterol increase the chance of a heart attack. In addition, the quality of the cholesterol-carrying LDL particles may influence the cardiovascular risk of a person.
We have recently developed a method for monitoring the quality of LDL particles in blood circulation by measuring the tendency of LDL particles to aggregate after their enzymatic treatment. Aggregation-prone LDL particles can accumulate in the arterial wall, where they may induce the formation of cholesterol-rich, inflamed plaques that can rupture and cause a heart attack. We have shown that LDL isolated from patients with known cardiovascular disease is more aggregation-prone than LDL isolated from healthy individuals. The most aggregation-prone LDL was found in those patients who later died because of cardiovascular disease.
We are currently examining the factors that influence the quality of LDL particles and other circulating lipoproteins and their accumulation in the arteries. Although lipoprotein quality is largely controlled by genetic factors, the quality can be improved by cholesterol-lowering medication or by a healthy diet. We are currently working on finding new ways to improve lipoprotein quality.
The root cause of atherosclerotic cardiovascular disease is entrapment of lipoproteins in the arterial intima and the ensuing local inflammation. Both processes are influenced by the composition of the extracellular matrix, activation of arterial cells, and lipoprotein quality and type. We examine the retention and accumulation of apolipoprotein (apo) B-containing particles, such as low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) in the arterial intima. Our research group has determined mechanisms of LDL aggregation. We have also reported on how modification and aggregation of lipoprotein particles influences their binding to components of the arterial wall and analysed the effect of various extracellular conditions on the modification and retention of LDL. We have also visualized aggregated lipoproteins in human lesions using state-of-the art mass spectrometric and electron microscopic techniques.
MODIFIED LIPOPROTEINS INDUCE INFLAMMATION
Aggregated lipoproteins from human atherosclerotic lesions and LDL-derived lipids, such as cholesterol crystals, induce foam cell formation and activate the inflammasome pathway in macrophages. We have discovered that acidic extracellular pH renders LDL particles susceptible for aggregation and induces the formation of extremely large LDL aggregates. Acidic pH enhances the interactions between LDL and extracellular matrix and promotes inflammasome activation. We have also shown that inflammasome components are present in human atherosclerotic lesions.
MEASUREMENT OF LDL AGGREGATION SUSCEPITIBILITY
Recently, we pioneered an assay to determine the quality of low-density lipoprotein (LDL) particles, based on their propensity to aggregate. We uncovered a strong link between aggregation-prone LDL and cardiovascular deaths in atherosclerotic patients. The aggregation susceptibility of LDL shows wide person-to-person variation, and the presence of aggregation-prone LDL predicts future cardiovascular events independently of conventional risk factors. Using various in vitro and in vivo models, we have shown that the lipid composition of LDL particles is causally associated with differences in LDL aggregation. We have also shown that LDL composition and aggregation susceptibility can be influenced by diet.
We are continuing our LDL aggregation studies using both experimental animals and human samples. We also study the cellular effects of modified and aggregated lipoproteins. Currently we examine the detailed mechanisms of LDL aggregation with the aim of understanding how we could inhibit LDL modification and ensuing particle aggregation.
Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study. Christensen JJ, Narverud I, Ruuth M, Heier M, Jauhiainen M, Ulven SM, Bogsrud MP, Kovanen PT, Halvorsen B, Oda MN, Wium C, Retterstøl K, Öörni K§, Holven KB§. (2021) J. Intern. Med. 290:1083-1097 doi: 10.1111/joim.13383
Overfeeding saturated fat increases LDL (Low-Density Lipoprotein) aggregation susceptibility while overfeeding unsaturated fat decreases proteoglycan-binding of lipoproteins. Ruuth M, Lahelma M, Luukkonen PK, Lorey MB, Qadri S, Sädevirta S, Hyötyläinen T, Kovanen PT, Hodson L, Yki-Järvinen H & Öörni K. (2021) Arterioscler. Thromb. Vasc. Biol. 11:2823-2836. doi: 10.1161/ATVBAHA.120.315766
Low-density lipoprotein aggregation predicts adverse cardiovascular events in peripheral artery disease. Heffron, S. P., Ruuth, M., Xia, Y., Hernandez, G., Rodriguez, C., Öörni, K.* & Berger, J. S.* (2021) Atherosclerosis 316:53-57. doi: 10.1016/j.atherosclerosis.2020.11.016
Lysophosphatidylcholine in phospholipase A 2-modified LDL triggers secretion of angiopoietin 2. Nguyen SD, Korhonen EA, Lorey MB, Hakanpää L, Mäyränpää MI, Kovanen PT, Saharinen P, Alitalo K & Öörni K. 2021, Atherosclerosis. 327:87-00. doi: 10.1016/j.atherosclerosis.2021.04.007
Plant stanol esters reduce LDL (Low-Density Lipoprotein) aggregation by altering LDL surface lipids: The BLOOD FLOW randomized intervention study. Ruuth M., Äikäs L., Tigistu-Sahle F., Käkelä R., Lindholm H., Simonen P., Kovanen P. T., Gylling H. & Öörni K. 2020, Arterioscler Thromb Vasc Biol. 40, 9 p. 2310–2321. doi: 10.1161/ATVBAHA.120.314329
LDL aggregation susceptibility is higher in healthy South Asian compared with white Caucasian men. Ruuth M., Janssen L. G. M., Äikäs L., Tigistu-Sahle F., Nahon K. J., Ritvos O., Ruhanen H., Käkelä R., Boon M. R., Öörni K.* & Rensen P. C. N.* Nov-Dec 2019 J Clin Lipidol. 13, 6, 910—912.e2. doi: 10.1016/j.jacl.2019.09.011.
Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Ruuth M., Nguyen S. D., Vihervaara T., Hilvo M., Laajala T. D., Kondadi P. K., Gisterå 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., Rudel L., Öörni A., Baumann M., Baruch A., Laaksonen R., Ketelhuth D. F. J., Aittokallio T., Jauhiainen M., Käkelä R., Borén J., Williams K. J., Kovanen P. T., Öörni K. Jul 14, 2018, Eur Heart J. 39, 27, p. 2562–2573. doi: 10.1093/eurheartj/ehy319.
Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding. Maaninka K., Nguyen S. D., Mäyränpää M. I., Plihtari R., Rajamäki K., Lindsberg P. J., Kovanen P. T. & Öörni K. Aug 2018 Atherosclerosis. 275 p. 390–399. doi: 10.1016/j.atherosclerosis.2018.04.016.
Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties. Lehti S., Nguyen S. D., Belevich I., Vihinen H., Heikkilä H. M., Soliymani R., Käkelä R., Saksi J., Jauhiainen M., Grabowski G. A., Kummu O., Hörkkö S., Baumann M., Lindsberg P. J., Jokitalo E., Kovanen P. T. & Öörni K. Feb 2018, Am J Pathol. 188, 2, p. 525–538. doi: 10.1016/j.ajpath.2017.09.019.
p38δ MAPK: A novel regulator of NLRP3 inflammasome activation with increased expression in coronary atherogenesis. Rajamäki K., Mäyränpää M. I., Risco A., Tuimala J., Nurmi K., Cuenda A., Eklund K. K., Öörni K. & Kovanen P. T. Sep 2016 Arterioscler Thromb Vasc Biol. 36, 9. p. 1937-1946. doi: 10.1161/ATVBAHA.115.307312.
Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation.Nguyen S. D., Javanainen M., Rissanen S., Zhao H., Huusko J., Kivelä A. M., Ylä-Herttuala S., Navab M., Fogelman A. M., Vattulainen I., Kovanen P. T. & Öörni K. Jun 2015 J Lipid Res. 56, 6, p. 1206–1221. doi: 10.1194/jlr.M059485.
Spatial distributions of lipids in atherosclerosis of human coronary arteries studied by time-of-flight secondary ion mass spectrometry. Lehti S., Sjövall P., Käkelä R., Mäyränpää M. I., Kovanen P. T. &Öörni K. May 2015 Am J Pathol. 2015, 185, 5, p. 1216–1233. doi: 10.1016/j.ajpath.2015.01.026.
CURRENT GROUP MEMBERS
Martin Hermansson Ph.D., post-doctoral researcher
Martina Lorey Ph.D., post-doctoral researcher
Lauri Äikäs, M.Sc., Ph.D researcher
Alina Iakubovskaia, M.Sc., Ph.D. researcher
Anni Niemelä, M.Sc. Tech., research assistant
Maija Atuegwu, Laboratory technician
FORMER GROUP MEMBERS
Elina Tonteri, Med. Student
Aurora Vikström, Med. StudentSu Duy Nguyen, Ph.D., Adj. Prof.,
Maija Ruuth, Ph.D., University of Helsinki, completed thesis in the group 2020
Katariina Maaninka, Ph.D., University of Helsinki, completed thesis in the group 2018
Satu Lehti, Ph.D., completed thesis in the group 2017
Kristiina Rajamäki, Ph.D., completed thesis in the group 2016
Riia Plihtari, Ph.D., completed thesis in the group 2010
Katariina Lähdesmäki, Ph.D., completed thesis in the group 2010
Tiia Kittilä, completed MSc thesis in the group
Mia Sneck, completed MSc thesis in the group
Aapeli Kemppainen, completed BMed thesis in the group 2019