Behavior of intracellular lipid droplets during cell division in HuH7 hepatoma cells.

Intracellular lipid droplets (LDs) are ubiquitous organelles found in many cell types. During mitosis, membranous organelles, including mitochondria, are divided into small pieces and transferred to daughter cells; however, the process of LD transfer to daughter cells is not fully elucidated. Herein, we investigated the behavior of LDs during mitosis in HuH7 human hepatoma cells. While fragments of the Golgi apparatus were scattered in the cytosol during mitosis, intracellular LDs retained their size and spherical morphology as they translocated to the two daughter cells. LDs were initially distributed throughout the cell during prophase but positioned outside the spindle in metaphase, aligning at the far sides of the centrioles. A similar distribution of LDs during mitosis was observed in another hepatocarcinoma HepG2 cells. When the spindle was disrupted by nocodazole treatment or never in mitosis gene A-related kinase 2A knockdown, LDs were localized in the area outside the chromosomes, suggesting that spindle formation is not necessary for LD localization at metaphase. The amount of major LD protein perilipin 2 reduced while LDs were enriched in perilipin 3 during mitosis, indicating the potential alteration of LD protein composition. Conclusively, the behavior of LDs during mitosis is distinct from that of other organelles in hepatocytes.

The Oxidized Lipoproteins In Vivo: Its Diversity and Behavior in the Human Circulation.

A high concentration of low-density lipoproteins (LDLs) in circulation has been well-known as a major risk factor for cardiovascular diseases. The presence of oxidized LDLs (oxLDLs) in atherosclerotic lesions and circulation was demonstrated using anti-oxLDL monoclonal antibodies. The so-called "oxLDL hypothesis", as a mechanism for atherosclerosis development, has been attracting attention for decades. However, the oxLDL has been considered a hypothetical particle since the oxLDL present in vivo has not been fully characterized. Several chemically modified LDLs have been proposed to mimic oxLDLs. Some of the subfractions of LDL, especially Lp(a) and electronegative LDL, have been characterized as oxLDL candidates as oxidized phospholipids that stimulate vascular cells. Oxidized high-density lipoprotein (oxHDL) and oxLDL were discovered immunologically in vivo. Recently, an oxLDL-oxHDL complex was found in human plasma, suggesting the involvement of HDLs in the oxidative modification of lipoproteins in vivo. In this review, we summarize our understanding of oxidized lipoproteins and propose a novel standpoint to understand the oxidized lipoproteins present in vivo.

Sar1 Affects the Localization of Perilipin 2 to Lipid Droplets.

Lipid droplets (LDs) are intracellular organelles that are ubiquitous in many types of cells. The LD core consists of triacylglycerols (TGs) surrounded by a phospholipid monolayer and surface proteins such as perilipin 2 (PLIN2). Although TGs accumulate in the phospholipid bilayer of the endoplasmic reticulum (ER) and subsequently nascent LDs buds from ER, the mechanism by which LD proteins are transported to LD particles is not fully understood. Sar1 is a GTPase known as a regulator of coat protein complex Ⅱ (COPⅡ) vesicle budding, and its role in LD formation was investigated in this study. HuH7 human hepatoma cells were infected with adenoviral particles containing genes coding GFP fused with wild-type Sar1 (Sar1 WT) or a GTPase mutant form (Sar1 H79G). When HuH7 cells were treated with oleic acid, Sar1 WT formed a ring-like structure around the LDs. The transient expression of Sar1 did not significantly alter the levels of TG and PLIN2 in the cells. However, the localization of PLIN2 to the LDs decreased in the cells expressing Sar1 H79G. Furthermore, the effects of Sar1 on PLIN2 localization to the LDs were verified by the suppression of endogenous Sar1 using the short hairpin RNA technique. In conclusion, it was found that Sar1 has some roles in the intracellular distribution of PLIN2 to LDs in liver cells.

High-Density Lipoprotein Suppresses Neutrophil Extracellular Traps Enhanced by Oxidized Low-Density Lipoprotein or Oxidized Phospholipids.

Neutrophil extracellular traps (NETs) are found in patients with various diseases, including cardiovascular diseases. We previously reported that copper-oxidized low-density lipoprotein (oxLDL) promotes NET formation of neutrophils, and that the resulting NETs increase the inflammatory responses of endothelial cells. In this study, we investigated the effects of high-density lipoproteins (HDL) on NET formation. HL-60-derived neutrophils were treated with phorbol 12-myristate 13-acetate (PMA) and further incubated with oxLDL and various concentrations of HDL for 2 h. NET formation was evaluated by quantifying extracellular DNA and myeloperoxidase. We found that the addition of native HDL partially decreased NET formation of neutrophils induced by oxLDL. This effect of HDL was lost when HDL was oxidized. We showed that oxidized phosphatidylcholines and lysophosphatidylcholine, which are generated in oxLDL, promoted NET formation of PMA-primed neutrophils, and NET formation by these products was completely blocked by native HDL. Furthermore, we found that an electronegative subfraction of LDL, LDL(-), which is separated from human plasma and is thought to be an in vivo oxLDL, was capable of promoting NET formation. These results suggest that plasma lipoproteins and their oxidative modifications play multiple roles in promoting NET formation, and that HDL acts as a suppressor of this response.

Circulating oxidized LDL, increased in patients with acute myocardial infarction, is accompanied by heavily modified HDL.

Oxidized LDL (oxLDL) is a known risk factor for atherogenesis. This study aimed to reveal structural features of oxLDL present in human circulation related to atherosclerosis. When LDL was fractionated on an anion-exchange column, in vivo-oxLDL, detected by the anti-oxidized PC (oxPC) mAb, was recovered in flow-through and electronegative LDL [LDL(-)] fractions. The amount of the electronegative in vivo-oxLDL, namely oxLDL in the LDL(-) fraction, present in patients with acute MI was 3-fold higher than that observed in healthy subjects. Surprisingly, the LDL(-) fraction contained apoA1 in addition to apoB, and HDL-sized particles were observed with transmission electron microscopy. In LDL(-) fractions, acrolein adducts were identified at all lysine residues in apoA1, with only a small number of acrolein-modified residues identified in apoB. The amount of oxPC adducts of apoB was higher in the LDL(-) than in the L1 fraction, as determined using Western blotting. The electronegative in vivo-oxLDL was immunologically purified from the LDL(-) fraction with an anti-oxPC mAb. The majority of PC species were not oxidized, whereas oxPC and lysoPC did not accumulate. Here, we propose that there are two types of in vivo-oxLDL in human circulating plasma and the electronegative in vivo-oxLDL accompanies oxidized HDL.

Comparison of protein profiles of the pellicle, gingival crevicular fluid, and saliva: possible origin of pellicle proteins.

BACKGROUND: The pellicle, the acellular organic material deposited on the surface of tooth enamel, has been thought to be derived from saliva. In this study, protein compositions of the pellicle, gingival crevicular fluid, and saliva collected from healthy adults were compared to elucidate the origin of pellicle proteins. RESULTS: The pellicle, gingival crevicular fluid, and saliva from the parotid gland or mixed gland were collected; subsequently, protein expression in samples from the respective individual was compared by SDS-PAGE and mass spectrometry. Following SDS-PAGE, proteins in the major bands were identified by mass spectrometry. The band pattern of pellicle proteins appeared different from those of gingival crevicular fluid, or saliva samples. Using mass spectrometry, 13 proteins in these samples were identified. The relative abundance of the proteins was quantitatively analyzed using mass spectrometry coupled with stable isotope labeling and by western blot. Cystatin S and α-amylase detected in pellicle were enriched in saliva samples, but not in gingival crevicular fluid, by western blot, and their abundance ratios were high in saliva and low in gingival crevicular fluid when analyzed by stable isotope labeling. Serotransferrin, however, was found only in the pellicle and gingival crevicular fluid by western blot and its abundance ratio was low in saliva. CONCLUSIONS: Our study revealed that the gingival crevicular fluid appears to contribute to pellicle formation in addition to saliva.

Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography-tandem mass spectrometry.

AIM: Laser microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) enable clinicians to analyse proteins from tissue sections. In nephrology, these methods are used to diagnose diseases of abnormal protein deposition, such as amyloidosis, but they are seldom applied to the diagnosis and pathophysiological understanding of human glomerular diseases. METHODS: Renal biopsy specimens were obtained from five patients with IgA nephropathy (IgAN), five patients with membranous nephropathy (MN) and five kidney transplant donors (as controls). From 10-µm-thick sections of formalin-fixed, paraffin-embedded specimens, 0.3-mm2 samples of glomerular tissue were subjected to LMD. The samples were analysed by LC-MS/MS and investigated clinically and histologically. RESULTS: From the control glomeruli, we identified more than 300 types of proteins. In patients with IgAN, we detected significant increases not only in IgA1 and in C3, but also in the factors related to oxidative stress and cell proliferation in comparison to the controls. In patients with MN, levels of IgG1, IgG4, C3, C4a and phospholipase-A2-receptor were significantly elevated in comparison to the controls, as were the aforementioned factors related to oxidative stress and cell proliferations detected in IgAN. CONCLUSION: Application of LMD and LC-MS/MS to renal biopsy specimens enabled us to identify not only pathognomonic proteins for the diagnosis, but also several factors possibly involved in the pathogenesis of human glomerular diseases.

Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases.

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.

Hypertension Enhances Advanced Atherosclerosis and Induces Cardiac Death in Watanabe Heritable Hyperlipidemic Rabbits.

Hypertension is a major risk factor for the development of atherosclerosis. Cardiovascular risk has been reported to be significantly increased in hyperlipidemic patients with hypertension. However, it is not clear whether hypertension can directly destabilize plaques, thereby enhancing cardiovascular events. To examine whether hypertension enhances the development of atherosclerosis and increases plaque vulnerability, we generated hypertensive Watanabe heritable hyperlipidemic (WHHL) rabbits by surgical removal of one kidney and partial ligation of the other renal artery and compared the nature of aortic and coronary atherosclerosis in hypertensive WHHL rabbits with normotensive WHHL rabbits. All hypertensive WHHL rabbits died from 34 to 56 weeks after surgery, whereas no normotensive WHHL rabbits died. Pathologic examinations revealed that hypertensive WHHL rabbits showed different degrees of myocardial infarction caused by severe coronary stenosis along with myocardial hypertrophy. Furthermore, aortic lesions in hypertensive WHHL rabbits exhibited a higher frequency of intraplaque hemorrhage and vulnerable plaques than those in normotensive WHHL rabbits. These results indicate that hypertension induced by the surgical removal of one kidney and partial ligation of the other renal artery method in WHHL rabbits may not only enhance the development of atherosclerosis but also destabilize the plaques, increasing cardiac death.

A Standard Intervention Practice to Promote Appropriate Lamotrigine Therapy by Pharmacists.

The dosage and frequency of lamotrigine administration for each patient must be prescribed carefully according to the disease, age, concomitant medications, and administration period. According to Pharmaceuticals and Medical Devices Agency (PMDA) reports, either the number of patients with adverse events caused by the inappropriate use of lamotrigine or the ratio of the patients who have benefited from the Relief System for Adverse Drug Reactions did not change even after the revision of the package insert in 2015. The procedure for auditing lamotrigine prescriptions was standardized to improve patient safety in our hospitals. The efficacy of standardization was evaluated by investigating the patients' records and prescriptions. A total of 77 patients treated with lamotrigine were examined to evaluate the appropriateness of the dosage and frequency of administration as well as the number of prescription enquiries made by pharmacists retrospectively. In addition, the presence of adverse events such as skin rash was examined using medical records. The number of inappropriate cases found and the prescription questions asked by pharmacists during the 24-month period before and after standardization were compared. The rate of inappropriate prescriptions after standardization was significantly lower than that before (12.1 vs. 29%; p<0.05). The rate of prescription questions raised after standardization was significantly higher than that before (37.0 vs. 1.7%; p<0.05). Moreover, there was no adverse event after standardization. Our standardization practice was effective to easily identify inappropriate prescriptions and provide physicians with the appropriate dosage or frequency of administration for the patients.

Quantitative proteomic analysis of gingival crevicular fluids from deciduous and permanent teeth.

AIM: Gingivitis commonly progresses to periodontitis in permanent dentition but rarely in deciduous teeth. Little is known about the biochemical differences between gingiva of deciduous and permanent teeth. Here, we compared the protein profiles of gingival crevicular fluids (GCF) from the gingiva of deciduous and permanent teeth. MATERIALS AND METHODS: Forty children with mixed dentition (Hellman's dental age IIIA) were selected and GCF samples were collected from deciduous cuspids and central incisors in the maxilla. Pairs of GCF samples were labelled using isobaric tags to permit quantitative comparison of protein abundance in the samples using liquid chromatography-electron spray ionization-tandem mass spectrometry. RESULTS: Sixty-two proteins were upregulated in deciduous teeth GCF and 54 in permanent teeth GCF. In particular, neutrophil-derived proteins, including myeloperoxidase and lactoferrin, were repeatedly higher in deciduous teeth GCF than in permanent teeth GCF. These differences were verified using ELISA (p < 0.01). In contrast, immunoglobulin components were upregulated in permanent teeth GCF. CONCLUSIONS: Neutrophil-related proteins were enriched in deciduous teeth GCF and immunoglobulins in permanent teeth GCF. This suggests that neutrophil accumulation plays a protective role in innate immunity against bacterial infection in gingival tissue of deciduous teeth.

Perilipins: a diversity of intracellular lipid droplet proteins.

Intracellular lipid droplets (LDs) are found in a wide variety of cell types and have been recognized as organelles with unique spherical structures. Although LDs are not stable lipid-depots, they are active sites of neutral lipid metabolism, and comprise neutral lipid or cholesterol cores surrounded by phospholipid monolayers containing specialized proteins. However, sizes and protein compositions vary between cell and tissue types. Proteins of the perilipin family have been associated with surfaces of LDs and all carry a conserved 11-mer repeat motif. Accumulating evidence indicates that all perilipins are involved in LD formation and that all play roles in LD function under differing conditions. In this brief review, we summarize current knowledge of the roles of perilipins and lipid metabolizing enzymes in a variety of mammalian cell types.

Characterization of lipid droplets in steroidogenic MLTC-1 Leydig cells: Protein profiles and the morphological change induced by hormone stimulation.

Lipid droplets (LDs) are functional subcellular organelles involved in multiple intracellular processes. LDs are found in nearly all types of eukaryotic cells, but their properties are highly variable in different types of tissues. Steroidogenic cells synthesize steroid hormones de novo from the cholesterol deposited in cytosolic LDs. However, the roles of LD proteins in steroidogenesis under pituitary hormone stimulation have not been well elucidated. The protein profile of isolated LDs from the mouse Leydig tumor cell line MLTC-1 was distinct from that of hepatic cells or macrophages. By proteomic analysis of the components using mass spectrometry, two enzymes for steroidogenesis, 3ß-hydroxysteroid dehydrogenase type 1 (3ßHSD1) and 17 ß-hydroxysteroid dehydrogenase type 11 (17ßHSD11), were identified in two strong bands in the LD fractions. The LD fraction of MLTC-1 cells also included CYP11A1 and CYP17, suggesting that the LDs contain all the enzymes needed for testosterone synthesis. The steroidogenesis in Leydig cells is activated by luteinizing hormone through a PKA-dependent pathway. Stimulation of MLTC-1 cells with luteinizing hormone or 8-bromo-cAMP caused drastic changes in the morphology of the LDs in the MLTC-1 cells. Upon stimulation, large perinuclear LDs are turned into much smaller LDs and dispersed throughout the cytosol. These results raise the possibility that LDs are involved in a regulatory pathway of steroidogenesis, not just by serving as a storage depot for cholesterol esters, but also by providing enzymes and generating sites for enzymatic activity.

Nephronectin Expression Is Up-Regulated by BMP-2.

Nephronectin (Npnt), known to be a ligand of integrin α8ß1, plays important roles in the development and function of various tissues, including those of the kidneys, liver, bones, and muscles. In previous studies, we showed that the expression of Npnt mRNA was regulated by various cytokines, including transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α), and oncostatin M (OSM), and that over-expression of Npnt enhanced osteoblast differentiation. In this study, we found that bone morphogenic protein-2 (BMP-2), known as an osteogenesis inducing cytokine, strongly up-regulated the expression of Npnt mRNA in a murine skeletal muscle cell line (C2C12) via the BMP-SMAD signaling pathway.

Olanzapine promotes the accumulation of lipid droplets and the expression of multiple perilipins in human adipocytes.

Second generation antipsychotics are useful for the treatment of schizophrenia, but concerns have been raised about the side effects of diabetes mellitus and obesity. Olanzapine, especially, is associated with more weight gain than the others. It has been reported that olanzapine promotes adipocyte-differentiation in rodents both in vivo and in vitro. In this study the effects of antipsychotics on human adipocytes were investigated by using human mesenchymal stem cells (hMSCs). When hMSCs were differentiated and treated with various antipsychotics, olanzapine and clozapine increased intracellular lipids. Olanzapine induced lipid accumulation in a dose-dependent manner. Proteomic analysis revealed that PLIN4 and several enzymes for lipid metabolism were increased in the hMSCs after olanzapine treatment. During adipocyte differentiation, olanzapine increased the protein expression of PLIN1, PLIN2 and PLIN4. These proteins are known to be associated with the initial stage of lipid droplet formation. Immunocytochemistry showed that olanzapine increased and enlarged the lipid droplets coated with PLIN1 and PLIN2 while PLIN4 was largely distributed in the cytosol. mRNA expression of PLIN2, but not PLIN1 or PLIN4, was increased by olanzapine. On the other hand, olanzapine did not alter the mRNA level of transcription regulators involved in adipocyte-differentiation or adipokines. The present study shows that olanzapine induced transient PLIN2 expression in hMSCs that could result in an accumulation of lipid droplets and overexpression of PLIN1 and PLIN4, providing information of possible interest for olanzapine-induced weight gain.

Dietary cholesterol atherogenic changes in juvenile rabbits.

Atherosclerotic lesion formation starts during fetal development and progresses with age after adolescence. However, atherogenesis during the juvenile period has not been studied thoroughly. In this study, we examined the atherogenic susceptibility of juvenile rabbits to cholesterol feeding. Male New Zealand White rabbits aged 8 (younger group) and 12 (older group) weeks were fed a 0.5% cholesterol-containing diet for 8 weeks, and then their aortic atherosclerotic lesion areas were evaluated. Plasma concentrations of total cholesterol, triglycerides, and phospholipids did not differ between the two groups; however, plasma concentrations of high-density lipoprotein cholesterol were 23% lower in the younger than in the older group. Atherosclerotic lesion areas were significantly larger in the younger group (32±21%). However, only moderate changes were observed in these areas in the older group (3.3±0.3%). Histological examination showed marked intimal thickening and macrophage accumulation in the aortic lesions of rabbits in the younger group. To the best of our knowledge, this is the first study to show that dietary cholesterol-induced atherogenic changes markedly occur during a short period in juvenile rabbits.

Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.

Time course-changes in phosphatidylcholine profile during oxidative modification of low-density lipoprotein.

BACKGROUND: Oxidized phosphatidylcholines (oxPC) and lysophosphatidylcholine (lysoPC) generated during the formation of oxidized low-density lipoprotein (oxLDL) are involved in atherosclerotic lesion development. We investigated the time course-changes in phosphatidylcholine (PC) molecular species during oxidation of LDL to determine how those atherogenic PCs are produced. METHODS: Human and rabbit LDLs were pretreated with or without a selective platelet-activating factor acetylhydrolase (PAF-AH) inhibitor. LDL was oxidized by incubation with copper sulfate, and PC profiles were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: When human LDL was oxidized, the peak areas for polyunsaturated fatty acid (PUFA)-containing PC species dramatically decreased after a short lag period, concomitantly lysoPC species increased sharply. Although a variety of oxPC species containing oxidized fatty acyl groups or cleaved acyl chains are formed during LDL oxidation, only a few oxPC products accumulated in oxLDL: 1-palmitoyl-2-(9-oxo-nonanoyl) PC and long-chain oxPC with two double bonds. Pretreatment of LDL with the PAF-AH inhibitor greatly reduced lysoPC production while it had no effect on lipid peroxidation reactions and oxPC profiles. Rabbit LDL, which has a different composition of PC molecular species and needs a longer time to reach achieve full oxidation than human LDL, also accumulated lysoPC during oxidation. The increase in lysoPC in rabbit oxLDL was suppressed by pretreatment with the PAF-AH inhibitor. The major oxPC species formed in rabbit oxLDL were almost the same as human oxLDL. CONCLUSIONS: These results suggest that lysoPC species are the major products and PAF-AH activity is crucial for lysoPC generation during oxidation of LDL. The oxPC species accumulated are limited when LDL is oxidized with copper ion in vitro.

Chronic kidney disease is associated with neovascularization and intraplaque hemorrhage in coronary atherosclerosis in elders: results from the Hisayama Study.

There is little information regarding whether patients with chronic kidney disease (CKD) have a high incidence of vulnerable plaques in their coronary arteries. To gain additional evidence on this, we conducted a population-based study by randomly selecting 126 subjects from 844 consecutive autopsies of elderly residents of Hisayama, Japan. We then determined the relationships of CKD with neovascularization and intraplaque hemorrhage in coronary atherosclerosis with the subjects classified into four categories based on their estimated glomerular filtration rate (eGFR). Areas of oxidized low-density lipoprotein (oxLDL) and vascular endothelial growth factor (VEGF) expression, assessed by immunohistochemistry in a total of 375 coronary arteries, increased significantly with decreasing eGFR. A lower eGFR was also associated with increased numbers of newly formed blood vessels. These relationships remained substantially unchanged after adjustment for confounding factors. The multivariate-adjusted odds ratio of the presence of intraplaque hemorrhages was 6.2 (95% confidence interval, 1.1-35.0) in patients with an eGFR <30 ml/min/1.73 m(2) compared with those with an eGFR of ≥ 60 ml/min/1.73 m(2). Thus, elderly patients with CKD have intimal neoangiogenesis and an increased risk of intraplaque hemorrhage in coronary arteries, possibly favored by local accumulation of oxLDL and VEGF.

The etiological consideration of oxidized low-density lipoprotein in periodontitis.

BACKGROUND: Epidemiologically, correlations between periodontal disease activity and CVD/serum lipid-related condition have been reported. Known mediators of these links include triglycerides, oxidized LDL (oxLDL) and inflammatory cytokines such as TNF-α supplied by adipocytes as well as oxidative degeneration products of these lipids. In this review, we focused on oxidized LDL and considered the relationship between periodontal disease and systemic conditions. HIGHLIGHT: The degree of oxidation in the periodontal pocket can be evaluated by analyzing the Gingival Cervicular Fluid (GCF), which can be easily collected with paperpoint. The oxLDL/LDL ratio in GCF has been shown to be 17 times as high as that in blood, and IL-8 and IL-1ß were also abundantly found in GCF. Periodontal treatment significantly lowers oxLDL levels in not only GCF but also plasma. In addition, there has been growing body of evidence that periodontal infections by periodontopathic bacteria affect arteriosclerosis. On the other hands, neutrophil extracellular traps (NETs), a form of innate immune responses, reportedly play a role as a defense mechanism in the periodontal pockets. However, the regulatory mechanism of NETs in periodontal pocket is still unknown. Recently, NETs induced by oxidized cholesterol have been reported to be involved in inflammatory damage to vascular endothelial cells. CONCLUSION: Further understanding of the newly discovered roles of oxLDL in the defense and destruction of periodontal tissues are anticipated.