Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein

Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.

Integrin Affinity Modulation Critically Regulates Atherogenic Endothelial Activation in vitro and in vivo

While vital to platelet and leukocyte adhesion, the role of integrin affinity modulation in adherent cells remains controversial. In endothelial cells, atheroprone hemodynamics and oxidized lipoproteins drive an increase in the high affinity conformation of α5β1 integrins in endothelial cells in vitro, and α5β1 integrin inhibitors reduce proinflammatory endothelial activation to these stimuli in vitro and in vivo. However, the importance of α5β1 integrin affinity modulation to endothelial phenotype remains unknown. We now show that endothelial cells (talin1 L325R) unable to induce high affinity integrins initially adhere and spread, but show significant defects in nascent adhesion formation. In contrast, overall focal adhesion number, area, and composition in stably adherent cells are similar between talin1 wildtype and talin1 L325R endothelial cells. However, talin1 L325R endothelial cells fail to induce high affinity α5β1 integrins, fibronectin deposition, and proinflammatory responses to atheroprone hemodynamics and oxidized lipoproteins. Inducing the high affinity conformation of α5β1 integrins in talin1 L325R cells partially restores fibronectin deposition, whereas NF-κB activation and maximal fibronectin deposition require both integrin activation and other integrin-independent signaling. In endothelial-specific talin1 L325R mice, atheroprone hemodynamics fail to promote inflammation and macrophage recruitment, demonstrating a vital role for integrin activation in regulating endothelial phenotype.

The role of subclinical hypothyroidism in lipid metabolism disorders

Subclinical hypothyroidism is common in general practice. The clinical significance of latent thyroid dysfunction has not yet been determined. The parameters of lipid metabolism and oxidative stress were studied in patients suffering from subclinical hypothyroidism between the ages of 18 and 50 years. They had a level of thyroid stimulating hormone ≥4 mIU/l, the level of free thyroxine was normal. The control group consisted of healthy individuals with thyroid-stimulating hormone level of 0,4-2,4 mIU/l. Thyroid status, thyroid peroxidase antibodies, lipid profile, malondialdehyde-modified low-density oxidized lipoproteins, antibodies to low-density oxidized lipoproteins, homocysteine were determined for all individuals. With the repeated determination of thyroid-stimulating hormone in 16,8% patients spontaneous recovery of thyroid-stimulating blood hormone level was observed, which was associated with lower values of thyroid-stimulating hormone and the absence of thyroid peroxidase antibodies. In the group of patients with thyroid stimulating hormone levels ≥7 mIU/l, the total cholesterol level was significantly (p=0,02) higher than in the control group. In patients with elevated values of malondialdehyde-modified oxidized low-density lipoprotein, thyroid stimulating hormone level of ≥7 mIU/l was more frequently detected. A negative correlation was found between the level of IgG antibodies to low-density oxidized lipoproteins and the concentration of free thyroxin. In the control group, the correlation was found between the concentration of IgG antibodies to low-density oxidized lipoproteins and the level of thyroid-stimulating hormone. In the group of subclinical hypothyroidism, the concentration of homocysteine was significantly (p=0,01) higher in men. In patients with subclinical hypothyroidism, more often hyperhomocysteinemia was detected compared with the control group. The results suggest that subclinical hypothyroidism is associated with initial changes in the metabolism of lipids and homocysteine.

Antimalarial Activity of Human Group IIA Secreted Phospholipase A2 in Relation to Enzymatic Hydrolysis of Oxidized Lipoproteins

ABSTRACT The level of human group IIA secreted phospholipase A2 (hGIIA sPLA2) is increased in the plasma of malaria patients, but its role is unknown. In parasite culture with normal plasma, hGIIA is inactive against Plasmodium falciparum, contrasting with hGIIF, hGV, and hGX sPLA2s, which readily hydrolyze plasma lipoproteins, release nonesterified fatty acids (NEFAs), and inhibit parasite growth. Here, we revisited the anti-Plasmodium activity of hGIIA under conditions closer to those of malaria physiopathology where lipoproteins are oxidized. In parasite culture containing oxidized lipoproteins, hGIIA sPLA2 was inhibitory, with a 50% inhibitory concentration value of 150.0 ± 40.8 nM, in accordance with its capacity to release NEFAs from oxidized particles. With oxidized lipoproteins, hGIIF, hGV, and hGX sPLA2s were also more potent, by 4.6-, 2.1-, and 1.9-fold, respectively. Using specific immunoassays, we found that hGIIA sPLA2 is increased in plasma from 41 patients with malaria over levels for healthy donors (median [interquartile range], 1.6 [0.7 to 3.4] nM versus 0.0 [0.0 to 0.1] nM, respectively; P < 0.0001). Other sPLA2s were not detected. Malaria plasma, but not normal plasma, contains oxidized lipoproteins and was inhibitory to P. falciparum when spiked with hGIIA sPLA2. Injection of recombinant hGIIA into mice infected with P. chabaudi reduced the peak of parasitemia, and this was effective only when the level of plasma peroxidation was increased during infection. In conclusion, we propose that malaria-induced oxidation of lipoproteins converts these into a preferential substrate for hGIIA sPLA2, promoting its parasite-killing effect. This mechanism may contribute to host defense against P. falciparum in malaria where high levels of hGIIA are observed.

Effects of a lifestyle intervention on markers of cardiometabolic risk and oxidized lipoproteins among obese adolescents with prediabetes

ObjectiveObesity and hyperglycaemia contribute to the atherosclerotic process in part through oxidative modifications to lipoprotein particles. The present study aimed to evaluate the effects of a lifestyle intervention on markers of oxidized lipoproteins in obese Latino adolescents with prediabetes.DesignPre–post design.SettingParticipants were enrolled into a 12-week lifestyle intervention. Measurements pre- and post-intervention included anthropometrics and body composition, lipid panel, oxidized LDL (oxLDL), oxidized HDL (oxHDL), intake of fresh fruits and vegetables, and cardiorespiratory fitness.ParticipantsThirty-five obese Latino adolescents (seventeen females, eighteen males; mean age 15·5 (sd1·0) years; mean BMI percentile 98·5 (sd1·2)) with prediabetes.ResultsIntervention participation resulted in significant reductions in weight (−1·2 %,P= 0·042), BMI and BMI percentile (−2·0 and −0·4 %, respectively,P< 0·001), body fat (−7·0 %,P= 0·025), TAG (−11·8 %,P= 0·032), total cholesterol (−5·0 %,P= 0·002), VLDL-cholesterol (−12·5 %,P= 0·029), and non-HDL-cholesterol (−6·7 %,P= 0·007). Additionally, fitness (6·4 %,P< 0·001) and intake of fruits and vegetables (42·4 %,P= 0·025) increased significantly. OxLDL decreased significantly after the intervention (51·0 (sd14·0)v. 48·7 (sd12·8) U/l,P= 0·022), while oxHDL trended towards a significant increase (395·2 (sd94·6)v. 416·1 (sd98·4) ng/ml,P= 0·056).ConclusionsThese data support the utility of lifestyle intervention to improve the atherogenic phenotype of Latino adolescents who are at high risk for developing premature CVD and type 2 diabetes.