Protective Effects Of High-density Lipoprotein Research Articles

Understanding Factors That Cause Benign Paroxysmal Positional Vertigo, Ménière Disease, and Vestibular Neuritis: A Two-Sample Mendelian Randomization Study.

Vertigo is a prevalent clinical symptom, frequently associated with benign paroxysmal positional vertigo (BPPV), Ménière disease (MD), and vestibular neuritis (VN), which are three common peripheral vestibular disorders. However, there is a relative lack of research in epidemiology and etiology, with some existing studies presenting discrepancies in their conclusions. We conducted a two-sample Mendelian randomization (MR) analysis to explore potential risk and protective factors for these three peripheral vestibular disorders. Based on genome-wide association studies, we executed a univariable MR to investigate the potential associations between 38 phenotypes and MD, BPPV, and VN. We used the inverse variance weighted method as the primary MR result and conducted multiple sensitivity analyses. We used false discovery rate (FDR) correction to control for type I errors. For findings that were significant in the univariable MR, a multivariable MR analysis was implemented to ascertain direct effects. In addition, we replicated analyses of significant results from the univariable MR to enhance the robustness of our analyses. For BPPV, both alcohol consumption (odds ratio [OR] = 0.57, 95% confidence interval [CI] = 0.43 to 0.76, FDR Q = 0.004) and educational attainment (OR = 0.77, 95% CI = 0.68 to 0.88, FDR Q = 0.003) were found to decrease the risk. The genetic prediction analysis identified major depression (OR = 1.75, 95% CI = 1.28 to 2.39, FDR Q = 0.008) and anxiety (OR = 5.25, 95% CI = 1.79 to 15.42, FDR Q = 0.036) increased the risk of MD. However, the impact of major depression on MD could be influenced by potential horizontal pleiotropy. Systolic blood pressures (OR = 1.03, 95% CI = 1.02 to 1.04, FDR Q = 4.00 × 10 -7 ) and diastolic blood pressures (OR = 1.05, 95% CI = 1.03 to 1.07, FDR Q = 2.83 × 10 -6 ) were associated with an increased risk of VN, whereas high-density lipoprotein (OR = 0.77, 95% CI = 0.67 to 0.89, FDR Q = 0.009) and urate (OR = 0.75, 95% CI = 0.63 to 0.91, FDR Q = 0.041) reduces the risk of VN. Only the relationship between urate and VN was not replicated in the replication analysis. Multivariable MR showed that the protective effect of education on BPPV was independent of Townsend deprivation index. The protective effect of high-density lipoprotein against VN was independent of triglycerides and apolipoprotein A1. The risk impacts of systolic and diastolic blood pressures on VN exhibited collinearity, but both are independent of chronic kidney disease and estimated glomerular filtration rate. The impacts of anxiety and severe depression on MD demonstrated collinearity. Our study identified the risk association between systolic and diastolic blood pressure with VN and the protective influence of high-density lipoprotein on VN, which may support the vascular hypothesis underlying VN. Furthermore, we observed an elevated risk of MD associated with anxiety. The potential protective effects of education and alcohol consumption on BPPV need further exploration in subsequent studies to elucidate specific mechanistic pathways. In summary, our MR study offers novel insights into the etiology of three peripheral vestibular diseases from a genetic epidemiological standpoint.

Depression and cognition are associated with lipid dysregulation in both a multigenerational study of depression and the National Health and Nutrition Examination Survey

Chronic dysregulation of peripheral lipids has been found to be associated with depression and cognition, but their interaction has not been investigated. Growing evidence has highlighted the association between peripheral lipoprotein levels with depression and cognition with inconsistent results. We assessed the association between peripheral lipids, depression, and cognition while evaluating their potential interactions using robust clinically relevant predictors such as lipoprotein levels and chronic medical disorders that dysregulate lipoproteins. We report an association between peripheral lipids, depression, and cognition, suggesting a common underlying biological mechanism driven by lipid dysregulation in two independent studies. Analysis of a longitudinal study of a cohort at high or low familial risk for major depressive disorder (MDD) (n = 526) found metabolic diseases, including diabetes, hypertension, and other cardiovascular diseases, were associated with MDD and cognitive outcomes. Investigating a cross-sectional population survey of adults in the National Health and Nutrition Examination Survey 2011–2014 (NHANES) (n = 2377), depression was found to be associated with high density lipoprotein (HDL) and cognitive assessments. In the familial risk study, medical conditions were found to be associated with chronic lipid dysregulation and were significantly associated with MDD using the structural equation model. A positive association between chronic lipid dysregulation and cognitive scores was found in an exploratory analysis of the familial risk study. In a complementary study, analysis of NHANES revealed a positive association of HDL levels with cognition. Further analysis of the NHANES cohort indicated that depression status mediated the interaction between HDL levels and cognitive tests. Importantly, the protective effect of HDL on cognition was absent in those with depressive symptoms, which may ultimately result in worse outcomes leading to cognitive decline. These findings highlight the potential for the early predictive value of medical conditions with chronic lipid dyshomeostasis for the risk of depression and cognitive decline.

Protective Effects of High-Density Lipoprotein on Cancer Risk: Focus on Multiple Myeloma.

Lipid metabolism is intrinsically linked to tumorigenesis. And one of the most important characteristics of cancer is the modification of lipid metabolism and its correlation with oncogenic signaling pathways within the tumors. Because lipids function as signaling molecules, membrane structures, and energy sources, lipids are essential to the development of cancer. Above all, the proper immune response of tumor cells depends on the control of lipid metabolism. Changes in metabolism can modify systems that regulate carcinogenesis, such as inflammation, oxidative stress, and angiogenesis. The dependence of various malignancies on lipid metabolism varies. This review delves into the modifications to lipid metabolism that take place in cancer, specifically focusing on multiple myeloma. The review illustrates how changes in different lipid pathways impact the growth, survival, and drug-responsiveness of multiple myeloma cells, in addition to their interactions with other cells within the tumor microenvironment. The phenotype of malignant plasma cells can be affected by lipid vulnerabilities, and these findings offer a new avenue for understanding this process. Additionally, they identify novel druggable pathways that have a major bearing on multiple myeloma care.

High-Density Lipoprotein and Heart Failure.

The protective effect of high-density lipoprotein (HDL) on atherosclerosis is well known, and its mechanisms of action has been extensively studied. However, the impact of HDL on heart failure and its mechanisms are still controversial or unknown. The cardioprotective role of HDL may be reflected in its antioxidant, anti-inflammatory, anti-apoptotic, and endothelial function protection. In epidemiological studies, high-density lipoprotein cholesterol (HDL-C) levels have been negatively associated with heart failure (HF). The major protein component of HDL-C is apolipoprotein (Apo) A-I, while paraoxonase-1 (PON-1) is an essential mediator for many protective functions of HDL, and HDL may act through components like (Apo) A-I or PON-1 to delay heart failure progress. HDL can slow heart failure disease progression through parts like (Apo) A-I or PON-1. The potential causality between HDL and heart failure, the role of HDL in the pathogenesis of HF, and its interaction with C-reactive protein (CRP), triglycerides (TG), and monocytes in the process of heart failure have been briefly summarized and discussed in this article. HDL plays an important role in the pathogenesis, progression and treatment of HF.

Modulation of the Cellular microRNA Landscape: Contribution to the Protective Effects of High-Density Lipoproteins (HDL).

High-density lipoproteins (HDL) play an established role in protecting against cellular dysfunction in a variety of different disease contexts; however, harnessing this therapeutic potential has proved challenging due to the heterogeneous and relative instability of this lipoprotein and its variable cargo molecules. The purpose of this study is to examine the contribution of microRNA (miRNA; miR) sequences, either delivered directly or modulated endogenously, to these protective functions. This narrative review introduces the complex cargo carried by HDL, the protective functions associated with this lipoprotein, and the factors governing biogenesis, export and the uptake of microRNA. The possible mechanisms by which HDL can modulate the cellular miRNA landscape are considered, and the impact of key sequences modified by HDL is explored in diseases such as inflammation and immunity, wound healing, angiogenesis, dyslipidaemia, atherosclerosis and coronary heart disease, potentially offering new routes for therapeutic intervention.

Low HDL-Cholesterol Concentrations in Lung Transplant Candidates are Strongly Associated With One-Year Mortality After Lung Transplantation.

High-density lipoproteins (HDLs), whose main role is the reverse transport of cholesterol, also have pleiotropic anti-inflammatory, antioxidant, anti-apoptotic and anti-infectious properties. During sepsis, HDL cholesterol (HDL-C) concentration is low, HDL particle functionality is altered, and these modifications are correlated with poor outcomes. Based on the protective effects of HDL, we hypothesized that HDL-C levels could be associated with lung transplantation (LT) outcome. We thus looked for an association between basal HDL-C concentration and one-year mortality after LT. In this single-center prospective study including consecutive LTs from 2015 to 2020, 215 patients were included, essentially pulmonary fibrosis (47%) and chronic obstructive pulmonary disease (COPD) (38%) patients. Mortality rate at one-year was 23%. Basal HDL-C concentration stratified nonsurvivors to survivors at one-year (HDL-C = 1.26 [1.12-1.62] mmol/L vs. HDL-C = 1.55 [1.22-1.97] mmol/L, p = 0.006). Multivariate analysis confirmed that HDL-C concentration during the pretransplant assessment period was the only variable inversely associated with mortality. Moreover, mortality at one-year in patients with HDL-C concentrations ≤1.45mmol/L was significantly higher (log-rank test, p = 0.00085). In conclusion, low basal HDL-C concentrations in candidates for LT are strongly associated with mortality after LT. To better understand this association, further studies in this field are essential and, in particular, a better characterization of HDL particles seems necessary.

Lack of Neuroprotective Effects of High-Density Lipoprotein Therapy in Stroke under Acute Hyperglycemic Conditions.

Introduction: The pleiotropic protective effects of high-density lipoproteins (HDLs) on cerebral ischemia have never been tested under acute hyperglycemic conditions. The aim of this study is to evaluate the potential neuroprotective effect of HDL intracarotid injection in a mouse model of middle cerebral artery occlusion (MCAO) under hyperglycemic conditions. Methods: Forty-two mice were randomized to receive either an intracarotid injection of HDLs or saline. Acute hyperglycemia was induced by an intraperitoneal injection of glucose (2.2 g/kg) 20 min before MCAO. Infarct size (2,3,5-triphenyltetrazolium chloride (TTC)-staining), blood–brain barrier leakage (IgG infiltration), and hemorrhagic changes (hemoglobin assay by ELISA and hemorrhagic transformation score) were analyzed 24 h post-stroke. Brain tissue inflammation (IL-6 by ELISA, neutrophil infiltration and myeloperoxidase by immunohisto-fluorescence) and apoptosis (caspase 3 activation) were also assessed. Results: Intraperitoneal D-glucose injection allowed HDL- and saline-treated groups to reach a blood glucose level of 300 mg/dl in the acute phase of cerebral ischemia. HDL injection did not significantly reduce mortality (19% versus 29% in the saline-injected group) or cerebral infarct size (p = 0.25). Hemorrhagic transformations and inflammation parameters were not different between the two groups. In addition, HDL did not inhibit apoptosis under acute hyperglycemic conditions. Conclusion: We observed a nonsignificant decrease in cerebral infarct size in the HDL group. The deleterious consequences of reperfusion such as hemorrhagic transformation or inflammation were not improved by HDL infusion. In acute hyperglycemia, HDLs are not potent enough to counteract the adverse effects of hyperglycemia. The addition of antioxidants to therapeutic HDLs could improve their neuroprotective capacity.

The changing landscape of atherosclerosis.

Emerging evidence has spurred a considerable evolution of concepts relating to atherosclerosis, and has called into question many previous notions. Here I review this evidence, and discuss its implications for understanding of atherosclerosis. The risk of developing atherosclerosis is no longer concentrated in Western countries, and it is instead involved in the majority of deaths worldwide. Atherosclerosis now affects younger people, and more women and individuals from a diverse range of ethnic backgrounds, than was formerly the case. The risk factor profile has shifted as levels of low-density lipoprotein (LDL) cholesterol, blood pressure and smoking have decreased. Recent research has challenged the protective effects of high-density lipoprotein, and now focuseson triglyceride-rich lipoproteins in addition tolow-density lipoprotein as causal in atherosclerosis. Non-traditional drivers of atherosclerosis-such as disturbed sleep, physical inactivity,the microbiome, air pollution and environmental stress-have also gained attention. Inflammatory pathways and leukocytes link traditional and emerging risk factors alike to the altered behaviour of arterial wall cells. Probing the pathogenesis of atherosclerosis has highlighted the role of the bone marrow: somatic mutations in stem cells can cause clonal haematopoiesis, which represents a previously unrecognized but common and potent age-related contributor to the risk of developing cardiovascular disease. Characterizations of the mechanisms that underpin thrombotic complications of atherosclerosis have evolved beyond the 'vulnerable plaque' concept. These advances in our understanding of the biology of atherosclerosis have opened avenues to therapeutic interventions that promise toimprove the prevention and treatment of now-ubiquitous atherosclerotic diseases.

English

BACKGROUND Coronary artery disease is multifactorial in origin. Coronary artery disease predisposition is attributed to genetic factors also. Many gene polymorphisms are implicated out of which paraoxonase 1 (PON 1) gene is an important one. The product of paraoxonase gene is paraoxonase enzyme which is seen in serum associated with high density lipoprotein (HDL). This enzyme is mainly synthesised by the liver. The protective effect of HDL is attributed to the presence of such enzymes on it. Gln to Arg polymorphism at position 192 confers a risk of developing atherosclerosis and coronary artery disease (CAD). This study is done to assess the genotype distribution of PON 1 gene in CAD patients compared to healthy controls in a population from Kerala. METHODS The case group consists of 100 angiographically proven CAD patients with no history of hypertension, diabetes mellitus, hepatic disease or smoking. The control group had 100 healthy controls from the general population. PON 1 gene was amplified by a polymerase chain reaction (PCR) technique already reported and restriction fragment length polymorphism by the restriction enzyme Alwl was done to assess the polymorphism. to assess the polymorphism. RESULTS In this study, the frequency of heterozygous genotype QR was 86 % in control and 76 % in cases. Though there was no significant difference in allele distribution of Q or R, RR genotype was significantly higher in the case group ( 2 = 8.82; p value = .012). With binary logistic regression model, adjusting for age and sex, RR genotype is independently associated with CHD. Adjusted odds ratio of RR was 5.24 with 95 % confidence interval (CI) 1.41 - 19.47 for developing CHD (p < 0.05). CONCLUSIONS The RR genotype is more frequently seen in CAD patients than in controls. The QR genotype is more frequent than QQ or RR in both cases and controls. KEYWORDS Coronary Artery Disease, Paraoxonase, Gene Polymorphism

Protective effects of high-density lipoprotein on mice cardiomyocytes induced by oxygen and glucose deprivation through Akt signaling pathway

To investigate the protective effect of high-density lipoprotein (HDL) on the mice cardiac myocytes induced by oxygen and glucose deprivation (OGD). Cardiac cells of primary scavenger receptor-B1 knockout mice (SR-B1-/-) and normal C57 mice (SR-B1+/+) were obtained by protease digestion and differential adhesion method. (1) The two kinds of cells were divided into normal control group (Con group), OGD group, OGD+HDL group. Propidium iodide (PI) staining were used to determine the necrosis of cardiac myocytes. (2) SR-B1+/+ cardiac cells were divided into Con group, OGD group, OGD+HDL group, and phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) inhibitor LY294002 group. PI staining were used to determine the necrosis of cardiac myocytes. TUNEL staining was used to determine the cell apoptosis. The kit was used to determine the contents of MB isoenzyme of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) in the culture medium supernatant. The expressions of SR-B1 and Akt protein were determined by Western Blot. (1) In SR-B1+/+ cardiomyocytes, HDL could inhibit cell necrosis induced by OGD. There was no protective effect of HDL on OGD in the SR-B1-/- cardiomyocytes. (2) The study of SR-B1+/+ cells was showed that compared with Con group, necrotic cells were significantly increased and cell activity were significantly decreased, the cell viability were significantly decreased, the contents of LDH and CK-MB in supernatant were significantly increased, the expressions of phosphorylated Akt (p-Akt) and SR-B1 were significantly decreased in OGD group. Compared with OGD group, the number of necrotic cells in the OGD+HDL group was significantly decreased [PI positive cells rate: (26.71±5.94)% vs. (64.24±18.34)%], the cell activity was significantly increased [(63.84±6.95)% vs. (26.71±5.13)%], the contents of LDH and CK-MB in supernatant were significantly decreased [LDH (U/L): 896.3±161.5 vs. 1 568.3±243.5, CK-MB (U/L): 304.3±72.9 vs. 583.6±81.6], the expressions of p-Akt and SR-B1 were significantly increased (p-Akt/t-Akt: 0.84±0.13 vs. 0.18±0.06, SR-B1/β-actin: 1.23±0.19 vs. 0.09±0.02), with statistically significant differences (all P < 0.05). Compared with OGD+HDL group, necrotic cells in LY294002 group were increased, cell activity was decreased, LDH and CK-MB contents in supernatant were increased, p-Akt and SR-B1 expressions were decreased; there was no statistical difference between LY294002 group and OGD group. There was no significant difference in cell apoptosis among the 4 groups. HDL has protective effect on the mice myocardial cells. The mechanism may be related with the up regulation of the expression of SR-B1 protein by the activation of PI3K/Akt pathway.

High-density lipoproteins attenuate high glucose-impaired endothelial cell signaling and functions: potential implications for improved vascular repair in diabetes

BackgroundAbnormalities of endothelial cell function are proposed to be a critical factor underlying adverse cardiovascular outcomes in the setting of hyperglycaemia. While high-density lipoproteins (HDL) have been demonstrated to be cardioprotective, the impact on the endothelium in hyperglycaemia has not been fully elucidated.MethodsHuman umbilical vein endothelial cells (HUVECs) were exposed to high-glucose conditions using dextrose, the main isoform of glucose, and native HDL. HUVEC proliferation and migration were determined. The key signalling pathways that regulate endothelial cell function were also characterized.ResultsIncreasing concentrations of dextrose resulted in significant reductions in HUVEC proliferation, this was attenuated by coincubation with HDL. In support of this, HDL was also found to rescue dextrose impaired expression of PCNA and the activation (phosphorylation) of the key transcription factor for proliferation ERK. Dextrose also dose-dependently inhibited HUVEC migration, which was mitigated by co-incubation with HDL. Consistent with this, HDL prevented dextrose-induced inhibition of p38 phosphorylation, responsible for cell migration. Finally, phosphorylation of the pro-survival transcription factor Akt was dose-dependently inhibited by dextrose, however, this was completely rescued by co-administration with HDL.ConclusionDextrose-induced hyperglycaemia causes the impairment of endothelial cell proliferation and migration and inhibits the activation of ERK, p38 and Akt pathways. The protective effects of HDL in this milieu highlights the potential for HDL to improve vascular repair in patients with impaired glucose homeostasis.

Protective effect of HDL on NADPH oxidase-derived super oxide anion mediates hypoxia-induced cardiomyocyte apoptosis.

Cardiovascular diseases are the leading cause of death of death in Taiwan. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death. Coronary heart disease (CHD) occurs when plaque builds up in the coronary arteries to cause the ischemic heart disease which will enhance myocardial remodeling and also induce myocardial hypoxia. High density lipoprotein (HDL) has been proposed to have cardio-protective effects. Under hypoxic conditions (1%O2 for 24hr), in H9c2 cells, reactive oxygen species (ROS) is induced which leads to cardiomyocyte apoptosis and cardiac dysfunction. Therefore, the present study described the protective effect of HDL on hypoxia-induced cardiomyocyte damage. We investigated the NADPH oxidase-produced ROS-related signaling pathways and apoptosis in cardiomyocytes under hypoxia conditions. Results showed that the ROS mediated cardiac damage might occur via AT1 and PKC activation. Furthermore, hypoxia downregulated the survival protein (p-AKTser473) and anti-apoptotic protein (BCL2), whereas pro-apoptotic protein, Bax and caspase 3 were upregulated. These detrimental effects by ROS and apoptosis were prevented by HDL pretreatment. Our findings revealed the underlying molecular mechanism by which HDL suppresses the hypoxia-induced cardiomyocyte dysfunction. Further, we elucidated the role of HDL on preventing hypoxia induced cardiomyocyte apoptosis is mediated through the inhibition of NADPH oxidase-derived ROS.

High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway.

Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation.

Abstract 545: Differential mRNA Expression is Influenced by Apolipoprotein A-I in Order to Promote Foam Cell Regression

Atherosclerosis is a disease of both lipids and inflammatory immune cells. More specifically, elevated plasma levels of low-density lipoproteins (LDL) leads to migration of circulating monocytes into the artery wall. Lipid loaded monocyte cells subsequently proliferate in the arterial walls becoming macrophage foam cells; a hallmark of atherosclerotic lesions. A proposed mechanism of the protective effects of high-density lipoprotein (HDL) is apolipoprotein A-I (apo A-I) acting as a mediator of cholesterol efflux and subsequent foam cell regression. To better understand the biological changes stimulated by apo A-I treatment, differential expression analysis of microarray data was performed on spleen cells from apo A-I treated mice. LDL receptor null (LDLr -/- ) and LDL receptor and apo A-I null (LDLr -/- , apoA-I -/- ) mice were fed a western diet consisting of 0.2% cholesterol and 42% of calories as fat for 12 weeks. After 6 weeks of diet, a subset of mice for each genotype was subcutaneously injected with 200 micrograms of apo A-I 3 times a week for the remaining 6 weeks. The control group mice were subcutaneously injected with 200 micrograms of saline or BSA. Spleen cell RNA was isolated, purified, and analyzed for differential expression analysis using Illumina BeadArray Microarray Technology Analysis. Individual gene expression analysis for LDLr -/- , apoA-I -/- apo A-I treated mice showed 281 significantly differentially expressed genes compared to BSA treated mice. LDLr -/- A-I treated mice had 1502. Of the significant genes, 189 intersected across both genotypes. LDLr -/- , apoA-I -/- A-I mice showed 73 up-regulated and 116 down-regulated genes. Similarly, LDLr -/- A-I mice had 71 up-regulated and 118 down-regulated. One-directional Gene Set Enrichment Analysis (GSEA) of LDLr -/- , apoA-I -/- A-I mice revealed 49 significant pathways while a total of 63 were found for LDLr -/- . Of these pathways, 21 were up-regulated and 13 were down-regulated in both genotypes. Eight of the top 10 most significant up-regulated pathways in both genotypes were immune cell related. Their functions involve receptor, adhesion, and chemokine signaling. Overall, preliminary analysis suggests A-I treatment induces similar gene expression changes across different genotypes.

Protective Effects of HDL Against Ischemia/Reperfusion Injury.

Several lines of evidence suggest that, besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma high density lipoprotein (HDL) cholesterol level is also associated with short- and long-term unfavorable prognosis in patients, who have recovered from a myocardial infarction, suggesting a direct detrimental effect of low HDL on post-ischemic myocardial function. Experiments performed in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury have clearly shown that HDL are able to preserve cardiac function when given before ischemia or at reperfusion; the protective effects of HDL against I/R injury have been also confirmed in other tissues and organs, as brain and hind limb. HDL were shown to act on coronary endothelial cells, by limiting the increase of endothelium permeability and promoting vasodilation and neoangiogenesis, on white blood cells, by reducing their infiltration into the ischemic tissue and the release of pro-inflammatory and matrix-degrading molecules, and on cardiomyocytes, by preventing the activation of the apoptotic cascade. Synthetic HDL retains the cardioprotective activity of plasma-derived HDL and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures.

High-density lipoprotein: structural and functional changes under uremic conditions and the therapeutic consequences.

High-density lipoprotein (HDL) has attracted interest as a therapeutic target in cardiovascular diseases in recent years. Although many functional mechanisms of the vascular protective effects of HDL have been identified, increasing the HDL plasma level has not been successful in all patient cohorts with increased cardiovascular risk. The composition of the HDL particle is very complex and includes diverse lipids and proteins that can be modified in disease conditions. In patients with chronic kidney disease (CKD), the accumulation of uremic toxins, high oxidative stress, and chronic micro-inflammatory conditions contribute to changes in the HDL composition and may also account for protein/lipid modifications. These conditions are associated with a decreased protective function of HDL. Therefore, the HDL quantity and the functional quality of the particle must be considered. This review summarizes the current knowledge of dyslipidemia in CKD patients, the effects of lipid-modulating therapy, and the structural modifications of HDL that are associated with dysfunction.

High-Density Lipoprotein - A Hero, a Mirage, or a Witness?

Negative relationship between plasma high-density lipoprotein (HDL) levels and risk of cardiovascular disease (CVD) is a firmly established medical fact, but attempts to reproduce protective properties of HDL by pharmacologically elevating HDL levels were mostly unsuccessful. This conundrum presents a fundamental question: were the approaches used to raise HDL flawed or the protective effects of HDL are an epiphenomenon? Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT). Here, we argue that this mode of HDL elevation may be mechanistically different to natural mechanisms and thus be counterproductive. We further argue that independently of whether HDL is a driving force or a surrogate measure of the rate of RCT, approaches aimed at increasing HDL supply, rather than reducing its catabolism, would be most beneficial for speeding up RCT and improving protection against CVD.

High density lipoprotein from patients with valvular heart disease uncouples endothelial nitric oxide synthase

Normal high density lipoprotein (HDL) protects vascular function; however these protective effects of HDL may absent in valvular heart disease (VHD). Because vascular function plays an important role in maintaining the circulation post-cardiac surgery and some patients are difficult to stabilize, we hypothesized that a deleterious vascular effect of HDL may contribute to vascular dysfunction in VHD patients following surgery. HDL was isolated from age-match 28 healthy subjects and 84 patients with VHD and during cardiac surgery. HDL pro-inflammation index was measured and the effects of HDL on vasodilation, protein interaction, generation of nitric oxide (NO) and superoxide were determined. Patients with VHD received either simvastatin (20mg/d) or routine medications, and endothelial effects of HDL were characterized. HDL inflammation index significantly increased in VHD patients and post-cardiac surgery. HDL from VHD patients and post-cardiac surgery significantly impaired endothelium-dependent vasodilation, inhibited both Akt and endothelial nitric oxide synthase (eNOS) phosphorylation at S1177, eNOS associated with heat shock protein 90 (HSP90), NO production and increased eNOS phosphorylation at T495 and superoxide generation. Simvastatin therapy partially reduced HDL inflammation index, improved the capacity of HDL to stimulate eNOS and Akt phosphorylation at S1177, eNOS associated with HSP90, NO production, reduced eNOS phosphorylation at T495 and superoxide generation, and improved endothelium-dependent vasodilation. Our data demonstrated that HDL from VHD patients and cardiac surgery contributed to endothelial dysfunction through uncoupling of eNOS. This deleterious effect can be reversed by simvastatin, which improves the vasoprotective effects of HDL. Targeting HDL may be a therapeutic strategy for maintaining vascular function and improving the outcomes post-cardiac surgery.

High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3

High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.

Antioxidant status in patients with psoriasis.

Psoriasis is a chronic inflammatory skin disease with an unknown aetiology that has been associated with abnormal plasma lipid metabolism and oxidative stress. There are controversial results in the previous studies investigating oxidant/antioxidant systems in psoriasis.The aim of this work was to evaluate the plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total bilirubin (T. Bili), direct bilirubin (D. Bili), uric acid (UA), apolipoproteins (ApoA1 and ApoB), Lp(a) and activities of paraxonase 1 (PON1) in 100 patients with psoriasis and 100 controls, and to look for a correlation between these parameters in psoriasis.PON1, bilirubin and UA were measured spectrophotometrically, MDA by the high-performance liquid chromatography method, apolipoproteins and Lp(a) by immunoprecipitation assays, and lipid and other biochemical parameters were determined by routine laboratory methods.In patients with psoriasis, there was a significant decrease in PON1, SOD and CAT activities (P < 0.05) and an increase in MDA levels (P < 0.01). Also, the levels of bilirubin (total and direct) and UA were decreased in patients with psoriasis but were not significant (P > 0.05).These results suggest that psoriasis was in a state of oxidative stress and that the protective effects of high-density lipoprotein against atherosclerosis may be dependent on PON1 activity. Moreover, there is a negative correlation between antioxidant with Lp(a), apoB and MDA levels, suggesting that subjects with higher levels of Lp(a) and apoB and lower levels of antioxidant are more exposed to oxidative damage. These findings may explain in part the reported increase in cardiovascular mortality in psoriasis.