Papers by Katariina Öörni
Current Medicinal Chemistry, 2019
Apolipoprotein B –containing lipoproteins include triglyceride-rich lipoproteins (chylomicrons an... more Apolipoprotein B –containing lipoproteins include triglyceride-rich lipoproteins (chylomicrons and their remnants, and very low-density lipoproteins and their remnants) and cholesterol-rich low-density lipoprotein particles. Of these, lipoproteins having sizes below 70-80 nm may enter the arterial wall, where they accumulate and induce the formation of atherosclerotic lesions. The processes that lead to accumulation of lipoprotein-derived lipids in the arterial wall have been largely studied with a focus on the low-density lipoprotein particles. However, recent observational and genetic studies have discovered that the triglyceriderich lipoproteins and their remnants are linked with cardiovascular disease risk. In this review, we describe the potential mechanisms by which the triglyceride-rich remnant lipoproteins can contribute to the development of atherosclerotic lesions, and highlight the differences in the atherogenicity between low-density lipoproteins and the remnant lipoprot...
Journal of Clinical Medicine, 2021
Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to ... more Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle...
Phospholipase A 2 (PLA 2) enzymes are important in numerous physiological processes. Their functi... more Phospholipase A 2 (PLA 2) enzymes are important in numerous physiological processes. Their function at lipid-water interfaces is also used as a biophysical model for protein-membrane interactions. These enzymes catalyze the hydrolysis of the sn-2 bonds of various phospholipids and the hydrolysis products are known to increase the activity of the enzymes. Here, we have applied molecular dynamics (MD) simulations to study the membrane properties in three compositionally different systems that relate to PLA 2 enzyme action. One-nanosecond simulations were performed for a 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) bilayer and for two of its PLA 2-hydrolyzed versions, i.e., bilayers consisting of lysophospholipids and of either free charged linoleate or free uncharged linoleic acid molecules. The results revealed loosening of the structure in the hydrolyzed bilayer due to increased mobility of the molecules in the direction normal to the bilayer. This loss of integri...
iScience, 2021
Summary High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated pa... more Summary High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLs may lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger fo...
Journal of Lipid Research, 2021
Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Urs... more Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5–10 times lower binding to arterial...
The American Journal of Clinical Nutrition
Journal of Lipid Research
Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and th... more Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and thus conceivably could play a major role in vasculopathy-driven chronic graft failure and cardiovascular mortality in renal transplant recipients. The present study investigated whether lipoprotein-proteoglycan binding susceptibility (LPBS) of apoB-containing lipoproteins and levels of the classical atherosclerosis biomarker LDL-C were associated with cardiovascular mortality (n = 130) and graft failure (n = 73) in 589 renal transplant recipients who were followed up from at least 1 year after transplantation for 9.5 years. At baseline, LPBS was significantly higher in patients who subsequently developed graft failure than in those with a surviving graft (1.68 ± 0.93 vs. 1.46 ± 0.49 nmol/mmol, P = 0.001). Cox regression analysis showed an association between LPBS and chronic graft failure in an age- and sex-adjusted model (hazard ratio: 1.45; 95% CI, 1.14–1.85; P = 0.002), but no association was observed with cardiovascular mortality. LDL-C levels were not associated with graft failure or cardiovascular mortality. This study shows that measurement of cholesterol retention outperformed the traditionally used quantitative parameter of LDL-C levels in predicting graft failure, suggesting a higher relevance of proatherogenic function than the quantity of apoB-containing lipoproteins in chronic kidney graft failure.
Journal of Clinical Lipidology
BACKGROUND There is little knowledge on the effects of alpha-linolenic acid (ALA) and n-3 long-ch... more BACKGROUND There is little knowledge on the effects of alpha-linolenic acid (ALA) and n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) on the LDL lipidome and aggregation of LDL particles. OBJECTIVE We examined if consumption of Camelina sativa oil (CSO) as a source of ALA, fatty fish (FF) as a source of n-3 LCPUFA and lean fish (LF) as a source of fish protein affect the lipidome of LDL as compared to a control diet. METHODS Participants with impaired glucose tolerance (39 women and 40 men) were randomized to 4 study groups (CSO providing 10 g/d ALA, FF and LF [both 4 fish meals/wk] and control limiting their fish and ALA intake) in a 12-week, parallel trial. Diets were instructed and dietary fats were provided to the participants. The lipidome of LDL particles isolated from samples collected at baseline and after intervention was analyzed with electrospray ionization-tandem mass spectrometry. RESULTS In the CSO group, the relative concentrations of saturated and monounsaturated cholesteryl ester species in LDL decreased and the species with ALA increased. In the FF group, LDL phosphatidylcholine (PC) species containing n-3 LCPUFA increased. There was a significant positive correlation between the change in total sphingomyelin and change in LDL aggregation, while total PC and triunsaturated PC species were inversely associated with LDL aggregation when all the study participants were included in the analysis. CONCLUSION Dietary intake of CSO and FF modifies the LDL lipidome to contain more polyunsaturated and less saturated lipid species. The LDL surface lipids are associated with LDL aggregation.
Clinical & Translational Immunology
The NLRP3 inflammasome plays a key role in arterial wall inflammation. In this study, we elucidat... more The NLRP3 inflammasome plays a key role in arterial wall inflammation. In this study, we elucidated the role of serum lipoproteins in the regulation of NLRP3 inflammasome activation by serum amyloid A (SAA) and other inflammasome activators.
Atherosclerosis
The effect of intakes of fish and Camelina sativa oil on atherogenic and antiatherogenic function... more The effect of intakes of fish and Camelina sativa oil on atherogenic and antiatherogenic functions of LDL and HDL particles: A randomized controlled trial, Atherosclerosis,
Journal of the American Heart Association
Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE ‐IT [Improv... more Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE ‐IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycer...
Atherosclerosis, 2011
Objective: Familial hypercholesterolemia (FH) is associated with increased risk of premature athe... more Objective: Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis. Increasing evidence supports involvement of inflammation in atherogenesis. The inflammatory cytokine tumor necrosis factor (TNF)␣ has been regarded as a key mediator in the development of atherosclerosis due to its involvement in several stages in this process. We hypothesized that children with FH, as a model of early atherosclerosis, have different serum levels of inflammation markers than healthy control children. Methods: We measured serum levels of TNF␣, as well as its endogenous inhibitors (i.e., soluble TNF receptors [sTNFR] 1 and 2) and the anti-inflammatory cytokine interleukin (IL)-10 in healthy children (7-20 years) with (n = 102) and without (n = 48) heterozygote FH as well as adult FH subjects (n = 20) and healthy adult controls (n = 16). Results: The main findings were: Compared to control children, FH children had higher serum levels of TNF␣, accompanied by lower sTNFRs levels, resulting in an increased TNF␣/sTNFRs ratio (P < 0.05), potentially reflecting enhanced TNF␣ activity. In contrast to the increased TNF␣ levels, FH children had decreased serum levels of IL-10 (P < 0.01) resulting in an increased TNF␣/IL-10 ratio (P < 0.01). We did not observe any difference in the same parameters between adult subjects with and without FH. Conclusions: FH children are characterized by an inflammatory imbalance between TNF␣ and IL-10, potentially contributing to the accelerated atherosclerotic process in these individuals.
European heart journal, Jan 14, 2018
Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) thro... more 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. 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 phosphatidylch...
Nature Reviews Cardiology
Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balanc... more Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.Atherosclerosis is characterized by low-grade, chronic inflammation, and the balance between pro-inflammatory and inflammation-resolving mechanisms dictates the clinical outcomes. This Review discusses the specific causes of inflammation and the mechanisms underlying the impaired resolution of inflammation that characterize clinically dangerous atherosclerotic lesions and highlights the potential of pro-resolving mediator therapy for the prevention and treatment of atherosclerotic cardiovascular disease.Key pointsModified lipoproteins and cholesterol crystals accumulate in the arterial intima and induce foam cell formation and inflammation.Defective efferocytosis of apoptotic foam cells leads to necrotic core formation.Defective efferocytosis is a sign of failure in the resolution of inflammation.Inflammation resolution is mediated by specialized pro-resolving lipid mediators, proteins and signalling gases.Improvement of the balance between pro-inflammatory and pro-resolving processes enables the resolution of inflammation.Pro-resolving mediator therapy could be a novel approach to suppressing the formation of clinically dangerous atherosclerotic lesions.
Arteriosclerosis, Thrombosis, and Vascular Biology
Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprot... more Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity. Approach and Results: The participants (36 subjects; age, 48±10 years; body mass index, 30.9±6.2 kg/m 2 ) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL ag...
Arteriosclerosis, Thrombosis, and Vascular Biology
Objective: Plant stanol ester supplementation (2–3 g plant stanols/d) reduces plasma LDL (low-den... more Objective: Plant stanol ester supplementation (2–3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. Approach and Results: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to ...
Scientific Reports
Low-density lipoprotein (LDL) is considered the major risk factor for the development of atherosc... more Low-density lipoprotein (LDL) is considered the major risk factor for the development of atherosclerotic cardiovascular diseases (ASCVDs). A novel and rapid method for the isolation of LDL from human plasma was developed utilising affinity chromatography with monolithic stationary supports. The isolation method consisted of two polymeric monolithic disk columns, one immobilized with chondroitin-6-sulfate (C6S) and the other with apolipoprotein B-100 monoclonal antibody (anti-apoB-100 mAb). The first disk with C6S was targeted to remove chylomicrons, very-low-density lipoprotein (VLDL) particles, and their remnants including intermediate-density lipoprotein (IDL) particles, thus allowing the remaining major lipoprotein species, i.e. LDL, lipoprotein(a) (Lp(a)), and high-density lipoprotein (HDL) to flow to the anti-apoB-100 disk. The second disk captured LDL particles via the anti-apoB-100 mAb attached on the disk surface in a highly specific manner, permitting the selective LDL isolation. The success of LDL isolation was confirmed by different techniques including quartz crystal microbalance. In addition, the method developed gave comparable results with ultracentrifugation, conventionally used as a standard method. The reliable results achieved together with a short isolation time (less than 30 min) suggest the method to be suitable for clinically relevant LDL functional assays. Low-density lipoprotein (LDL) is a major cholesterol carrier in circulation. LDL is associated with the initiation and progression of atherosclerotic cardiovascular diseases due to particle remodeling and its retention within the subendothelial matrix and accumulation in subendothelial macrophages 1,2. The major apolipoprotein of the LDL particles, apolipoprotein B-100 (apoB-100), interacts tightly with the components of the extracellular matrix of the arterial intima thus enhancing its accumulation. In addition to LDL, the triglyceride-rich lipoproteins, including chylomicrons and VLDL remnants, are also capable of penetrating the arterial intima thus promoting atherogenesis 3-5. Rapid isolation of LDL particles from human plasma is crucially needed for their functional, lipidomic, and proteomic studies. Currently, the most employed method for the LDL isolation is based on ultracentrifugation 6,7. Major disadvantages of this method include being time-consuming, laborious, and prone to
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Papers by Katariina Öörni