👤 Petri T Kovanen

Elevated lipoprotein(a) [Lp(a)] is an important genetic risk factor for cardiovascular diseases (CVDs). Because Lp(a)-lowering therapies are limited, prevention focuses on identifying individuals with elevated Lp(a) and optimizing other modifiable risk factors. We aimed to assess the distribution of Lp(a) levels in Finnish adults and examine its association with other CVD risk factors, as well as the awareness, treatment, and control of dyslipidemia. Data were derived from the Healthy Finland health examination survey conducted in 2023, comprising a nationally representative sample of 5,484 adults. Lp(a) levels were categorized using a cut-point at 125 nmol/L. Other CVD risk factors included were dyslipidemia, abnormal glucose metabolism, hypertension, and obesity. Analyses were weighted taking into account the sampling design and non-participation to provide nationally representative results. Mean Lp(a) levels were 41.7 nmol/L (95% CI 39.0-44.3) in men (M) and 41.9 nmol/L (39.7-44.1) in women (W). Elevated Lp(a) was observed in 11.0% of men and 10.4% of women. Dyslipidemia was more prevalent among individuals with elevated Lp(a) (M: 88.1% vs. 78.4% p = 0.003, W: 79.2% vs. 73.2% p = 0.030) but this association reversed after correcting cholesterol for Lp(a). No associations were found between Lp(a) and other cardiometabolic risk factors. Individuals with elevated Lp(a) had slightly lower unawareness (M: 42.3% vs. 47.5%, p = 0.180, W: 38.8% vs.48.4%, p = 0.042) and better treatment (M: 38.1% vs. 31.7%, p = 0.010, W: 29.2% vs. 24.7%, p = 0.090) of dyslipidemia than those with lower levels while no association was found between Lp(a) and dyslipidemia control (M: 81.4% vs. 84.1%, p = 0.520, W: 74.6% vs. 73.0%, p = 0.740). Approximately one in ten Finnish adults had elevated Lp(a), a lower prevalence than in many other European populations but still affecting a substantial share of the population. Elevated Lp(a) was associated with higher prevalence of dyslipidemia prior to Lp(a) correction, but not with other CVD risk factors, and these individuals also showed slightly greater awareness and treatment of dyslipidemia. These findings emphasize the need for comprehensive management of modifiable CVD risk factors to reduce the overall burden of CVDs. Show less

BACKGROUNDIcosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), reduces cardiovascular disease (CVD), but the mechanism remains elusive. We examined the effect of IPE supplementation on lipoprotein subclasses, lipidomes, and pro-atherogenic properties.METHODSUsing 3 independent metabolomic platforms, we examined the effect of high-dose IPE supplementation for 28 days on fatty acid profiles, lipoprotein subclasses, lipidomes, and pro-atherogenic properties in normolipidemic volunteers (n = 38).RESULTSIPE supplementation increased lipoprotein EPA on average 4-fold within 7 days, returning to baseline after a 7-day washout. Notably, the incorporation displayed marked interindividual variance, negatively correlating with baseline levels. We identified persistent participant-specific lipoprotein fingerprints despite uniform IPE-induced lipidome remodeling across all lipoprotein classes. This remodeling resulted in reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids, resulting in reduced clinical risk markers, including triglyceride, remnant cholesterol, and apolipoprotein B (apoB) levels and 10-year CVD risk score. Of the pro-atherogenic properties tested, IPE significantly reduced apoB lipoprotein binding to proteoglycans, which correlated with lower apoB particle concentration, cholesterol content, and specific lipid species in LDL, including phosphatidylcholine 38:3 previously associated with CVD.CONCLUSIONThese findings highlight IPE's rapid, uniform remodeling of lipoproteins and reduced proteoglycan binding, likely contributing to previously observed CVD risk reduction. Persistent interindividual lipidome signatures underscore the potential for personalized therapeutic approaches in atherosclerotic CVD treatment.TRIAL REGISTRATIONNCT04152291.FUNDINGJenny and Antti Wihuri Foundation, Research Council of Finland, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Emil Aaltonen Foundation, Ida Montin Foundation, Novo Nordisk Foundation, Finnish Cultural Foundation, and Jane and Aatos Erkko Foundation. Show less

The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B-containing lipoproteins. Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article. Show less

Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood. To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. C57Bl/6J mice were exposed to restraint stress for 3 hours to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [(3)H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [(3)H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [(14)C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator-activated receptor-α increased, and that of the sterol influx transporter Niemann-Pick C1-like 1 decreased. The stress-dependent effects on RCT rate and peroxisome proliferator-activated receptor-α gene expression were fully mimicked by administration of the stress hormone corticosterone (CORT) to nonstressed mice, and they were blocked by the inhibition of CORT synthesis in stressed mice. Moreover, the intestinal expression of Niemann-Pick C1-like 1 protein decreased when circulating levels of CORT increased. Of note, when either peroxisome proliferator-activated receptor α or liver X receptor α knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma CORT increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT. Show less

T lymphocytes play a central role in controlling adaptive immune responses. IL-2 critically regulates both T cell growth and death and is involved in maintaining peripheral tolerance, but the molecules involved in these and other IL-2 actions are only partially known. We now provide a comprehensive compendium of the genes expressed in T cells and of those regulated by IL-2 based on a combination of DNA microarrays and serial analysis of gene expression (SAGE). The newly identified IL-2 target genes include many genes previously linked to apoptosis in other cellular systems that may contribute to IL-2-dependent survival functions. We also studied the mRNA expression of known regulators of signaling pathways for their induction in response to IL-2 in order to identify potential novel positive and/or negative feedback regulators of IL-2 signaling. We show that IL-2 regulates only a limited number of these genes. These include suppressors of cytokine signaling (SOCS) 1, SOCS2, dual-specificity phosphatase (DUSP) 5, DUSP6 and non-receptor type phosphatase-7 (PTPN7). Additionally, we provide evidence that many genes expressed in T cells locate in chromosomal clusters, and that select IL-2-regulated genes are located in at least two clusters, one at 5q31, a known cytokine gene cluster, and the other at 6p21.3, a region that contains genes encoding the tumor necrosis factor (TNF) superfamily members TNF, LT-alpha and LT-beta. Show less

In human atherosclerotic lesions, degranulated mast cells are found in the vicinity of macrophage foam cells. Mast cell granules contain tryptase, a tetrameric serine protease requiring glycosaminoglycans for stabilization. No endogenous inhibitors have been described for tryptase, and the physiological functions of the enzyme are poorly understood. Here, we investigated the effects of human tryptase on the integrity of high density lipoprotein (HDL)3 and on its ability to release cholesterol from cultured mouse macrophage foam cells. Incubation of HDL3 with tryptase led to degradation of its apolipoproteins. Tryptase predominantly degraded a quantitatively minor subfraction of HDL3 that is lipid poor, exhibits electrophoretic pre-beta mobility, and contains either apolipoprotein A-I or apolipoprotein A-IV as its sole apolipoprotein. Moreover, tryptase caused functional changes in HDL3 by destroying its ability to promote high-affinity efflux of cholesterol from macrophage foam cells, ie, the pre-beta-HDL-dependent component of the process. Human aortic proteoglycans increased the ability of tryptase to proteolyze HDL3, suggesting that the proteoglycan-rich extracellular matrix of the arterial intima provides an appropriate environment for the extracellular actions of tryptase. By depleting pre-beta-HDL, mast cell tryptase may impair the initial step of reverse cholesterol transport and will then favor cellular accumulation of cholesterol during atherogenesis. Show less