Relation between peripheral blood inflammatory indices and severity of central retinal artery occlusion.

Background: Central retinal artery occlusion (CRAO) has been identified as an acute emergency resulting in vision loss, with its pathogenesis potentially involving systemic inflammation and abnormal lipid metabolism. Over recent years, it has been established that peripheral blood inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), the systemic immunoinflammatory index (SII), and the monocyte-to-high-density lipoprotein ratio (MHR), play significant roles in assessing systemic inflammation and lipid metabolism. However, the role of these indices in assessing the severity of CRAO has rarely been explored. This study aimd to investigate the relationship between these inflammatory indices and the severity of CRAO. Methods: This was a retrospective clinical study with a total of 49 CRAO patients and 50 age- and sex-matched controls involved. The patients with CRAO were divided into three groups (13 with incomplete CRAO, 16 with subtotal CRAO and 20 with total CRAO). Data were compared across these groups, and additionally, correlation analysis, restricted cubic spline plots, and receiver operating characteristic curve analysis were performed. Results: The values of NLR, SII and MHR were significantly higher in the CRAO group compared to controls (NLR: 2.49(1.71,3.44) vs 1.60(1.24,1.97), P<0.001; SII: 606.46(410.25,864.35) vs 403.91(332.90,524.31), P=0.001; MHR: 0.33(0.26,0.44) vs 0.25(0.21,0.34), P<0.001). MHR was also significantly higher in total CRAO than in incomplete CRAO and subtotal CRAO (0.41(0.32,0.60) vs 0.29(0.21,0.43), P=0.036; 0.41(0.32,0.60) vs 0.29(0.23,0.38), P=0.017). Significant positive associations were found between MHR, NLR, SII and both the incidence (all P<0.001) and severity (P<0.001, P<0.001, P=0.003, respectively) of CRAO. MHR had a linear relationship with both the occurrence and severity of CRAO (P-overall=0.013, P-non-linear=0.427 and P-overall=0.013, P-non-linear=0.825). Combining MHR and NLR significantly improved diagnostic efficacy for CRAO and total CRAO, with area under the curve of 0.816 and 0.827, respectively, compared to using MHR alone (0.705 and 0.816). Conclusion: Elevated levels of peripheral blood NLR, SII, and MHR are positively associated with CRAO incidence, highlighting their potential as early predictive markers. The combined NLR and MHR index further enhances diagnostic accuracy and may facilitate timely assessment of CRAO severity by ophthalmologists and internists.

The Composition of the HDL Particle and Its Capacity to Remove Cellular Cholesterol Are Associated with a Reduced Risk of Developing Active Inflammatory Rheumatoid Arthritis.

In rheumatoid arthritis (RA), the risk of cardiovascular death is 50% higher compared to the general population. This increased risk is partly due to the systemic inflammation characteristic of RA and changes in the lipoprotein profiles. This study investigated plasma lipid levels, lipid ratios, and the composition and functionality of high-density lipoprotein (HDL) in control individuals and RA subjects based on the disease's inflammatory score (DAS28). This study included 50 control (CTR) individuals and 56 subjects with RA, divided into remission/low-activity disease (DAS28 < 3.2; n = 13) and active disease (DAS28 ≥ 3.2; n = 43). Plasma lipids (total cholesterol, TC; triglycerides, TG) and the HDL composition (TC; TG; phospholipids, PL) were determined using enzymatic methods; apolipoprotein B (apoB) and apoA-1 were measured by immunoturbidimetry. HDL-mediated cholesterol efflux and anti-inflammatory activity were assessed in bone marrow-derived macrophages. Comparisons were made using the Mann-Whitney test, and binary logistic regression was used to identify the predictors of active RA. A p-value < 0.05 was considered significant. TC, HDLc, and the TC/apoB ratio were higher in RA subjects compared to the CTR group. Subjects with active disease exhibited higher levels of TG and the TG/HDLc ratio and lower levels of HDLc, the TG/apoB ratio, TC, and apoA-1 in HDL particles compared to those with remission/low-activity RA. Increased levels of HDLc [odds ratio (OR) 0.931, 95% CI = 0.882-0.984], TC/apoB (OR 0.314, 95% CI = 0.126-0.78), HDL content in TC (OR 0.912, 95% CI = 0.853-0.976), PL (OR 0.973, 95% CI = 0.947-1.000), and apoA-1 (OR 0.932, 95% CI = 0.882-0.985) were associated with a decreased risk of active disease, but BMI (OR 1.169, 95% CI = 1.004-1.360) and TG (OR 1.031, 95% CI = 1.005-1.057) were positively associated with active disease. A reduction in HDL-mediated cholesterol efflux increased the OR for active RA by 26.2%. The plasma levels of HDLc, along with the composition and functionality of HDL, influence the inflammatory score in RA and may affect the development of cardiovascular disease.

Prevalence and clinical correlates of impaired fasting blood glucose in children and adolescents with depressive disorder and relationship with triglyceride and high-density lipoprotein ratio.

Depressive disorder is a significant public health problem worldwide, which adversely affects children and adolescents' health. Impaired fasting blood glucose (IFG) is more common in depressive disorder, which becomes a clinical problem that needs to be focused on. The study purposed to determine the prevalence and related factors of IFG in Chinese children and adolescents with depressive disorder and the relationship between triglyceride and high-density lipoprotein cholesterol (TG/HDL-C) ratio and IFG. This research encompassed 756 individuals aged 8 to 18 with major depressive disorders, all diagnosed under DSM-5 criteria at the Third People's Hospital of Fuyang from January 2020 to December 2021. We detected fasting blood glucose (FBG) and lipid levels and assessed the suicidal behaviors and depressive symptoms severity of each participant. The sociodemographic and included study variables were collected and analyzed. Our study employed multiple logistic regression to discern independent factors affecting IFG in conjunction with depressive disorders among children and adolescents. The prevalence of IFG was 6.5% (49/756). IFG was positively correlated with FBG, BMI, TG, TG/HDL-C, and was negatively correlated with gender and the type of antidepressant drug taken. Binary logistic analysis showed that male (OR = 2.57, 95% CI: 1.43-4.63, P = 0.002) and higher levels of TG (OR = 1.63, 95% CI: 1.11-2.38, P = 0.013) were independently associated with IFG in children and adolescents with depressive disorder. The incidence of IFG in children and adolescents with depressive disorder was high and was positively related to the TG/HDL-C ratio. The evaluation and management of IFG in pediatric depression should extend beyond pharmacological interventions. Comprehensive strategies in both assessment and management of IFG are essential to address this condition effectively in young patients facing depressive disorders.

High-density lipoprotein functionality in cholesterol efflux in early childhood is related to the content ratio of triglyceride to cholesterol.

Cholesterol efflux capacity (CEC), commonly measured as a useful risk marker of atherosclerotic cardiovascular disease, depends on high-density lipoprotein (HDL) functionality and its concentration. We defined the relative HDL functionality in cholesterol efflux, not influenced by HDL concentration, as the ratio of measured CEC to standardized CEC (stCEC) based on HDL-cholesterol (HDL-C) of each individual using the curve regression equation obtained from the correlation. HDL-C, CEC, and CEC/stCEC levels in the < 28-day-old participants (neonates) were significantly low compared to those of the ≥ 28-day-old participants, indicating that the low CEC levels in the neonates depend on not only lower HDL-C but also lower HDL functionality. The low level of CEC/stCEC was remarkable in neonates born at < 34 weeks of gestation and did not improved to the reference level (1.000) until the infantile period. The relatively low or high CEC/stCEC ratios in neonates and infants were associated with lower or higher HDL-TG and HDL-TG/HDL-C ratio, respectively. However, no apparent effect of HDL-TG and HDL-TG/HDL-C ratio on CEC/stCEC was observed in the ≥ 1-year-old participants, indicating that HDL functionality in cholesterol efflux could be associated with the various HDL particles with various lipid compositions, but not just with HDL-TG and HDL-TG/HDL-C ratio.

The association between serum HDL levels and infertility among American women aged 20-44 years: A retrospective cross-sectional study of NHANES, 2013-2020.

BACKGROUND: Infertility is a significant national public health concern, and the World Health Organization (WHO) predicts that it will rank as the third most prevalent disease following tumors, cardiovascular and cerebrovascular diseases. The impact of dysfunctional lipoproteins on female infertility remains relatively understudied; therefore, the research focuses on exploring the relationship between serum high-density lipoprotein (HDL) concentration and infertility. METHODS: This is a retrospective cross-sectional study where we employed multivariate logistic regression analysis to examine the association between serum HDL concentrations and female infertility. The strength of association was quantified using odds ratios (OR) along with their corresponding 95% confidence intervals and statistical significance was evaluated at a level of P < 0.05 (two-tailed). RESULTS: The study found that there was a significant correlation between serum HDL and infertility without adjusting the model (OR = 0.62, 95%CI 0.48-0.82, P<0.001). After adjusting for covariates, a weak correlation between HDL and infertility remained (OR = 0.70, 95%CI 0.49-1.00). When HDL concentrations were divided into quartiles, there was a trend of strengthened correlation between HDL and infertility risk with the increase in HDL concentrations. Specifically, individuals in the highest concentration quartile exhibited a 44.0% lower risk of infertility compared to those in the lowest concentration quartile (95% CI 0.38-0.84). In the age-stratified analysis, after adjusting for covariates, the correlation between HDL and infertility was statistically insignificant across all age groups. Furthermore, after categorizing HDL levels into quartiles, we observed a dose-dependent trend between HDL and the reduction of female infertility risk in the adjusted models of the secondary infertility group. Specifically, in the adjusted model, the high-concentration group exhibited a 67.0% lower risk of infertility compared to the low-concentration group (OR = 0.33; 95% CI: 0.12-0.940, P = 0.04). CONCLUSION: Our research findings suggest weak negative correlation between serum HDL and female infertility. However, upon stratified analysis by age, the correlation between HDL and infertility did not attain statistical significance. In cases of secondary infertility, a subtle dose-dependent trend was observed between serum HDL and infertility.

Impact of Vitamin E Supplementation on High-Density Lipoprotein in Patients With Haptoglobin Genotype-Stratified Diabetes: A Systematic Review of Randomized Controlled Trials.

Background: Vitamin E, an essential micronutrient with antioxidant potential, can dramatically reduce the cardiovascular risk in individuals with haptoglobin (Hp) 2-2 genotype diabetes; however, the underlying mechanism remains unclear. Objective: The objective of this study is to evaluate the effect of vitamin E supplementation on high-density lipoprotein (HDL) levels and function in individuals with diabetes stratified by Hp genotype. Methods: All relevant studies published up to May 2023 were systematically reviewed using PubMed, Cochrane Library, Web of Science, Chinese Wanfang, China Science and Technology Journal, and Chinese National Knowledge Infrastructure databases. Randomized controlled trials that evaluated the effects of vitamin E supplementation on HDL levels were included. The outcomes assessed were changes in HDL concentrations, cholesterol efflux, and HDL-associated lipid peroxides. Results: In total, 163 publications were selected. Based on inclusion and exclusion selection and quality assessment, five studies with 463 participants were included. Vitamin E supplementation did not exert any effect on HDL levels in individuals with diabetes with any Hp genotype. Three of the five studies revealed that vitamin E improved cholesterol efflux and HDL lipid peroxides in individuals with Hp2-2 diabetes but did not positively impact HDL function in Hp1 carriers. Conclusions: Although vitamin E supplementation did not significantly impact HDL levels in individuals with diabetes of any Hp genotype, it may improve HDL function in individuals with Hp2-2 diabetes. These findings indicate a pharmacogenetic interaction between vitamin E and the Hp genotype on HDL function. Moreover, vitamin E supplementation may be an effective strategy for specific individuals with diabetes.

High-Density Lipoprotein Mimetic Peptide 4F Reduces Toxic Amyloid-Beta Exposure to the Blood-Brain Barrier Endothelium in Alzheimer's Disease Transgenic Mice.

Aß accumulation in the blood-brain barrier (BBB) endothelium, which lines the cerebrovascular lumen, is a significant contributor to cerebrovascular dysfunction in Alzheimer's disease (AD). Reduced high-density lipoprotein (HDL) levels are associated with increased AD risk, and the HDL mimetic peptide 4F has been developed as a promising therapeutic agent to improve cerebrovascular health in AD. In this study, we evaluated the impact of 4F on 125I-Aß42 blood-to-brain distribution using dynamic SPECT/CT imaging in both wild-type and APP/PS1 transgenic mice. Graphical analysis of the imaging data demonstrated that 4F significantly reduced the blood-to-brain influx rate in wild-type mice and the distribution of 125I-Aß42 in the BBB endothelium in APP/PS1 mice. To elucidate the molecular mechanisms underlying the effect of 4F, we evaluated its impact on the p38 pathway and its role in mediating Aß42 trafficking in human BBB endothelial cell monolayers. Treatment with 4F significantly decreased Aß42 induced p38 activation in BBB endothelial cells. Furthermore, inhibition of p38 kinase significantly reduced endothelial accumulation of fluorescence-labeled Aß42 and luminal-to-abluminal permeability across the cell monolayer. While our previous publication has hinted at the potential of 4F to reduce Aß accumulation in the brain parenchyma, the current findings demonstrated the protective effect of 4F in reducing Aß42 accumulation in the BBB endothelium of AD transgenic mice. These findings revealed the impact of a clinically tested agent, the HDL mimetic peptide 4F, on Aß exposure to the BBB endothelium and offer novel mechanistic insights into potential therapeutic strategies to treat cerebrovascular dysfunction in AD.

Two-way Dispatched function in Sonic hedgehog shedding and transfer to high-density lipoproteins.

The Sonic hedgehog (Shh) signaling pathway controls embryonic development and tissue homeostasis after birth. This requires regulated solubilization of dual-lipidated, firmly plasma membrane-associated Shh precursors from producing cells. Although it is firmly established that the resistance-nodulation-division transporter Dispatched (Disp) drives this process, it is less clear how lipidated Shh solubilization from the plasma membrane is achieved. We have previously shown that Disp promotes proteolytic solubilization of Shh from its lipidated terminal peptide anchors. This process, termed shedding, converts tightly membrane-associated hydrophobic Shh precursors into delipidated soluble proteins. We show here that Disp-mediated Shh shedding is modulated by a serum factor that we identify as high-density lipoprotein (HDL). In addition to serving as a soluble sink for free membrane cholesterol, HDLs also accept the cholesterol-modified Shh peptide from Disp. The cholesteroylated Shh peptide is necessary and sufficient for Disp-mediated transfer because artificially cholesteroylated mCherry associates with HDL in a Disp-dependent manner, whereas an N-palmitoylated Shh variant lacking C-cholesterol does not. Disp-mediated Shh transfer to HDL is completed by proteolytic processing of the palmitoylated N-terminal membrane anchor. In contrast to dual-processed soluble Shh with moderate bioactivity, HDL-associated N-processed Shh is highly bioactive. We propose that the purpose of generating different soluble forms of Shh from the dual-lipidated precursor is to tune cellular responses in a tissue-type and time-specific manner.

Impaired HDL antioxidant and anti-inflammatory functions are linked to increased mortality in acute heart failure patients.

AIMS: Acute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood. METHODS: HDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin-cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. RESULTS: Among the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity. CONCLUSIONS: In patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.

Molecular mechanisms of the regulatory action of high-density lipoproteins on the endothelial function.

Endothelial dysfunction underlies the pathogenesis of many diseases, primarily cardiovascular diseases. Epidemiological studies have shown an inverse dependence between the plasma level of high-density lipoproteins (HDL) and cardiovascular diseases. The results of experimental studies indicate that the antiatherogenic effect of HDL is associated not only with their participation in the reverse transport of excess cholesterol, but also with their regulatory effect on the functions of cells of various organs and tissues, including endothelial cells. The purpose of this review is to consider recent data on the participation of plasma receptors and related intracellular signaling pathways in the mechanism of protective effect of HDL on endothelial cell functions. Understanding the mechanisms of cell function regulation under the influence of HDL is an important step for the development of new ways of pharmacological correction of impaired endothelial functions and creation of effective endothelial protection drugs.

Association between high-density lipoprotein-related inflammation index and periodontitis: insights from NHANES 2009-2014.

BACKGROUND: Periodontitis, a persistent inflammatory condition, significantly impairs individuals' overall quality of life. Lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), and platelet-to-high-density lipoprotein cholesterol ratio (PHR) are new convenient and economical biomarkers. However, whether the above high-density lipoprotein-related inflammatory biomarkers are associated with periodontitis has rarely been investigated. Therefore, the research endeavor focused on uncovering potential relationships. METHODS: The research encompassed a diverse and extensive sample, comprising 9,470 participants, selected from the National Health and Nutrition Examination Survey spanning the years 2009 to 2014. The association between high-density lipoprotein-related inflammatory biomarkers and periodontitis was explored utilizing a multivariable logistic regression model with weighted analysis. Additionally, the study employed smoothed curve fitting to explore potential nonlinear relationships. Further stratified analyses and interaction tests were performed. RESULTS: This study indicated no apparent association between MHR and PHR with periodontitis, whereas LHR and NHR demonstrated a statistically significant positive relationship with the prevalence of periodontitis. In the fully adjusted model, participants belonging to the highest tertile of both LHR and NHR showed a notably higher likelihood of having periodontitis compared to those in the lowest tertile (LHR: OR = 1.22, 95% CI: 1.06, 1.39; NHR: OR = 1.27, 95% CI: 1.09, 1.49). Furthermore, smooth curve fitting was employed to investigate the potential nonlinear relationship between LHR, NHR, and periodontitis. The results indicated that there was a significant increase in the occurrence of periodontitis when Log2 (LHR) exceeded 1.01 and Log2(NHR) surpassed 2.16 (Log2(LHR): OR = 1.42; 95% CI: 1.19, 1.69; Log2(NHR): OR = 1.40; 95% CI: 1.15, 1.71). The subgroup analysis revealed that the associations between periodontitis and either LHR or NHR, separately, were more pronounced among individuals under the age of 50 and those without hypertension. CONCLUSIONS: This cross-sectional study revealed a positive relationship between LHR、NHR and periodontitis, particularly when these indicators exceeded their thresholds. LHR and NHR may serve as potential inflammatory markers for identifying periodontitis, thereby facilitating early warning for both patients and dentists, and enabling early intervention in the oral environment. Besides, extensive prospective cohort investigations are essential to confirm and solidify this observation.

Increased oxidative stress biomarkers in central serous chorioretinopathy.

Current data suggest that oxidative stress may play an important role in the occurrence of acute central serous chorioretinopathy (CSC), as chorioretinal integrity may be affected by disruption of the patient's metabolic redox balance, indicating the need for biomarkers. In addition to oxidative stress, high-density lipoprotein (HDL) dysfunction due to dyslipidemia can also lead to many types of physical discomfort. However, little is known about the pathophysiology of the disease resulting from oxidative stress and HDL dysfunction in CSC. The aim of this study was to investigate whether serum oxidative stress and HDL functionality markers have an impact on CSC disease. The case series of this study included 33 consecutive patients with treatment-naïve acute CSC. Thirty-five healthy volunteers of similar age were included in this study as non-CSC controls. Serum samples of the participants were taken and routine lipid values, serum Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Oxidized Low Density Lipoprotein (ox-LDL), and Paraoxonase (PON1) levels were measured quantitatively. Serum oxidative stress index (OSI) was then calculated. Serum Ox-LDL, TOS and OSI levels in the acute CSC group, consisting of patients who had never been treated before and had no other disease, were statistically significantly higher than the control group. Conversely, serum PON1 and TAS levels were lower in CSC than in the control group. The relationship between CSC and deterioration in serum redox balance and decrease in PON1 activity, an important marker of HDL functionality, was demonstrated for the first time through this study. According to the literature, serum levels of these biomarkers, which identify acute/chronic inflammation and oxidative stress, have not been measured before in CSC disease. Finally, it is conceivable that redox balance and HDL functionality may be important in the diagnosis and treatment of the acute phase of CSC.

Favourable HDL composition in endurance athletes is not associated with changes in HDL in vitro antioxidant and endothelial anti-inflammatory function.

Given the failure of high-density lipoprotein (HDL) raising therapies to reduce cardiovascular disease risk, attention has turned towards HDL composition and vascular protective functions. In individuals with insulin resistance, exercise interventions recover HDL function. However, the effect of exercise on HDL in otherwise healthy individuals is unknown. This cross-sectional study aimed to measure HDL composition and antioxidant/endothelial anti-inflammatory function in insulin sensitive endurance athlete and healthy control men. HDL was isolated using density gradient ultracentrifugation. HDL composition was measured using microplate assays for apolipoprotein A-I, total cholesterol content and apolipoprotein M. HDL protein composition was measured using nano-liquid chromatography tandem mass spectrometry. HDL subclass distribution was measured by native gel electrophoresis. HDL in vitro antioxidant function was measured by paraoxonase-1 activity assay and anti-inflammatory function assessed in endothelial cells. Compared with controls, endurance athlete HDL had higher apolipoprotein A-1 (1.65 ± 0.62 mg/ml vs 1.21 ± 0.34 mg/ml, P=0.028) and higher total cholesterol content (2.09 ± 0.44 mmol/L vs 1.54 ± 0.33 mmol/L, P<0.001). Proteomics revealed higher apolipoprotein A-II, A-IV and D and transthyretin in endurance athlete HDL versus controls. There was no difference observed in in vitro HDL antioxidant or anti-inflammatory functions between controls and endurance athletes. Despite a more favourable composition, endurance athlete HDL did not have higher in vitro antioxidant or anti-inflammatory function. It is possible that HDL has a ceiling of function, i.e. that healthy HDL function cannot be enhanced by endurance exercise.

Impact of gluten-free diet (GFD) on some of cardiovascular risk factors: a systematic review and meta-analysis.

A gluten-free diet (GFD) may have a stronger potential impact on reducing cardiovascular (CV) risk factors, according to research evidence. We investigated the impact of GFD on CV risk variables by doing a systematic review and meta-analysis for this reason. We conducted a thorough database search starting on January 1, 2000, and ending on July 12, 2022. We used random-effects models to pool the data. Totally 19 articles met the eligible criteria and were included. Pooled findings indicated that intervention with GFD has a significantly beneficial effect on high-density lipoprotein (HDL) (WMD: 4.80 mg/dl, 95% CI: 2.09, 7.51, P = 0.001), systolic blood pressure (SBP) (WMD: -2.96 mmHg; 95% CI: -4.11, -1.81, P < 0.001), and C-reactive protein (CRP) (WMD: -0.40, mg/l, 95% CI: -0.67, -0.14, P = 0.002) levels. In celiac patients as well as with an intervention duration of more than 48 weeks, GFD increased TC and HDL compared to non-celiac patients and with an intervention duration lower than 48 weeks, respectively. The results of the present study showed that GFD can have a significant and beneficial effect on HDL, SBP, and CRP.

Hydrogen sulfide upregulates SIRT1 to inhibit ox-HDL-induced endothelial cell damage and mitochondrial dysfunction.

BACKGROUND: Under normal circumstances, high-density lipoprotein (HDL) is considered to have cardiovascular protective effects, but the impact of oxidized HDL (ox-HDL) on vascular endothelial function remains poorly understood. Mitochondrial function is closely related to endothelial function, and hydrogen sulfide (H2S) is a gas with endothelial protective properties. The novel hydrogen sulfide donor AP39 can target mitochondria to release H2S, but the combined effects of ox-HDL and AP39 on vascular endothelium are not well studied. METHODS: We established a cell model of ox-HDL-induced endothelial cell damage and mitochondrial dysfunction using human umbilical vein endothelial cells (HUVECs) and conducted AP39 pretreatment. The experiments confirmed the functional damage and mitochondrial dysfunction in HUVECs caused by ox-HDL. Additionally, to further explore the role of SIRT1 in AS, we analyzed SIRT1 expression in AS carotid artery tissue. This included the analysis of differentially expressed genes from AS-related datasets, presented through volcano plots and heatmaps, with enrichment analysis of downregulated genes in KEGG pathways and GO functions. Furthermore, we evaluated the differences in SIRT1 expression in coronary arteries with varying degrees of stenosis and in early and late-stage AS carotid artery tissues, and analyzed data from SIRT1 knockout mouse models. RESULTS: The experimental results indicate that AP39 effectively alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. MTT and CCK-8 assays showed that ox-HDL treatment led to decreased cell viability and proliferation in HUVECs, reduced eNOS expression, and significantly increased levels of ICAM-1, IL-6, and TNF-α, along with enhanced monocyte adhesion. These findings reveal the damaging effects of ox-HDL on HUVECs. Transcriptomic data indicated that while SIRT1 expression did not significantly differ in coronary arteries with varying degrees of stenosis, it was notably downregulated in AS carotid artery tissues, especially in late-stage AS tissues. KEGG pathway enrichment analysis revealed that SIRT1 downregulated genes were associated with processes such as vascular smooth muscle contraction, while GO analysis showed that these downregulated genes were involved in muscle system processes and muscle contraction functions, further confirming SIRT1's critical role in AS pathology. In transcriptomic data from the SIRT1 knockout mouse model, elevated levels of inflammation-related proteins IL-6 and TNF-α were observed after SIRT1 knockout, along with decreased expression of the chaperone protein PGC-1α. The expression of mitochondrial-related functional proteins Nrf2 and PGC-1α was positively correlated with SIRT1 expression, while inflammation-related proteins ICAM-1, IL-6, IL-20, and TNF-α were negatively correlated with SIRT1 expression. We further discovered that ox-HDL triggered mitochondrial dysfunction, as evidenced by reduced expression of Mfn2, Nrf2, PGC1-α, UCP-1, and SIRT1, corroborating the results from the previous database analysis. Additionally, mitochondrial dysfunction was characterized by decreased mitochondrial membrane potential (MMP), increased mitochondrial ROS levels, and reduced ATP content, further impacting cellular energy metabolism and respiratory function. Subsequent experimental results showed that the addition of AP39 mitigated these adverse effects, as evidenced by decreased levels of ICAM-1, IL-6, and TNF-α, increased eNOS expression, reduced monocyte adhesion, increased mitochondrial H2S content, and upregulated expression of SIRT1 protein associated with mitochondrial function, reduced ROS levels, and increased ATP content. Furthermore, validation experiments using the SIRT1 inhibitor EX527 confirmed that AP39 alleviated ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1 expression. CONCLUSION: Ox-HDL can induce damage and mitochondrial dysfunction in HUVECs, while AP39 inhibits ox-HDL-induced endothelial cell damage and mitochondrial dysfunction by upregulating SIRT1.

Relationships between HDL subpopulation proteome and HDL function in overweight/obese people with and without coronary heart disease.

BACKGROUND AND AIMS: The structure-function relationships of high-density lipoprotein (HDL) subpopulations are not well understood. Our aim was to examine the interrelationships between HDL particle proteome and HDL functionality in subjects with and without coronary heart disease (CHD). METHODS: We isolated 5 different HDL subpopulations based on charge, size, and apolipoprotein A1 (APOA1) content from the plasma of 33 overweight/obese CHD patients and 33 age-and body mass index (BMI)-matched CHD-free subjects. We measured the relative molar concentration of HDL-associated proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS) and assessed particle functionality. RESULTS: We quantified 110 proteins associated with the 5 APOA1-containing HDL subpopulations. The relative molar concentration of these proteins spanned five orders of magnitude. Only 10 proteins were present in >1% while 73 were present in <0.1% concentration. Only 6 of the 10 most abundant proteins were apolipoproteins. Interestingly, the largest (α-1) and the smallest (preß-1) HDL particles contained the most diverse proteomes. The protein composition of each HDL subpopulation was altered in CHD cases as compared to controls with the most prominent differences in preß-1 and α-1 particles. APOA2 concentration was positively correlated with preß-1 particle functionality (ABCA1-CEC/mg APOA1 in preß-1) (R2 = 0.42, p = 0.005), while APOE concentration was inversely correlated with large-HDL particle functionality (SRBI-CEC/mg APOA1 in α-1+α-2) (R2 = 0.18, p = 0.01). CONCLUSIONS: The protein composition of the different HDL subpopulations was altered differentially in CHD patients. The functionality of the small and large HDL particles correlated with the protein content of APOA2 and APOE, respectively. Our data indicate that distinct particle subspecies and specific particle associated proteins provide new information about the role of HDL in CHD.

Establishment and validation of a nomogram model containing a triglyceride-glucose index and neutrophil-to-high-density lipoprotein ratio for predicting major adverse cardiac events in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: To analyze the predictive value of the triglyceride-glucose (TyG) index and neutrophil-to-high-density lipoprotein ratio (NHR) for in-hospital major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI), and to establish an associated nomogram model. METHODS: In this retrospective study, we collected data from consecutive STEMI patients who underwent PCI from October 2019 to June 2023 at the Second People's Hospital of Hefei and the Second Affiliated Hospital of Anhui Medical University, as training and validation sets. Stepwise regression and multivariate logistic regression analysis were performed to screen independent risk factors, and a nomogram model was constructed and evaluated for its predictive efficacy. RESULTS: The TyG index, NHR, urea, diastolic blood pressure, hypertension, and left ventricular ejection fraction were independent risk factors for in-hospital MACE after PCI, and were used to construct the nomogram model. The C-index of the training and validation sets were 0.799 and 0.753, respectively, suggesting that the model discriminated well. Calibration and clinical decision curves also demonstrated that the nomogram model had good predictive power. CONCLUSION: In STEMI patients, increased TyG index and NHR were closely related to the occurrence of in-hospital MACE after PCI. Our constructed nomogram model has some value for predicting the occurrence of in-hospital MACE in STEMI patients.

The value of myeloperoxidase to high density lipoprotein ratio in predicting 90-day recurrence in patients with acute ischemic stroke.

OBJECTIVE: The ratio of myeloperoxidase to high-density lipoprotein (MPO/HDL) has become a novel inflammatory biomarker in the field of cardiovascular disease. MPO and HDL have been reported to be associated with inflammation and lipid metabolism after AIS. However, the effect of MPO/HDL on AIS recurrence has not been studied. We aimed to assess the value of MPO/HDL in predicting relapse 90 days after AIS. METHODS: A total of 363 patients diagnosed with AIS were followed up for 90 days. Patients were assessed for recurrence within 90 days after AIS. Univariate and multivariate analyses were performed to determine the association between MPO/HDL and relapse within 90 days in AIS patients. The receiver operating characteristic curve (ROC) was used to compare the predictive value of MPO, HDL and MPO/HDL for recurrence at 90 days after AIS. RESULTS: The proportion of recurrent stroke patients within 90 days was 6.61% (24/363). Recurrent stroke was associated with NIHSS, WBC, NEUT, UA, DD, Hcy, MPO, HDL, and MPO/HDL. After adjusting for potential confounders, the 90-day recurrence risk of AIS patients increased by 0.03 (P < 0.001) for each unit increase in MPO/HDL. The ROC curve constructed after correcting confounders found that compared with MPO(AUC=0.9698) and HDL(AUC=0.821), MPO/HDL showed the highest AUC value (AUC=0.9801), indicating that MPO/HDL levels had the highest predictive value for 90-day relapse in AIS patients. CONCLUSIONS: MPO and MPO/HDL were independently associated with relapse within 90 days of AIS. MPO/HDL may be an independent predictor of 90-day relapse in AIS patients.

The effect of dual antioxidant modification on oxidative stress resistance and anti-dysfunction of non-split HDL and recombinant HDL.

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.