Cholesterol Retention Research Articles

IL-6R (trans-signaling) is a key regulator of reverse cholesterol transport in lipid-laden macrophages

Atherosclerosis is a cardiovascular disease caused by cholesterol-laden arterial plaques. This study evaluated the correlation between interleukin-6 (IL-6), its receptors (IL6R/CD126), and glycoprotein 130 (gp130) alongside atherosclerosis biomarkers in a cohort of 142 subjects, equally divided between lean and obese individuals. Subsequent analyses used THP-1-derived macrophages to assess the biochemical impact of inhibiting IL-6 receptors. IL-6 secretion increased with atherosclerosis in obese subjects, while IL6R/CD126 and gp130 on monocytes decreased. Pharmacological gp130 inhibition altered lipid metabolism, increasing LDLR gene expression and cholesterol synthesis via SREBF2 and mevalonate kinase, along with HMG-CoA reductase at protein levels. gp130-deficient cells produced more cholesterol and had lower ABCA1 levels, suggesting hindered cholesterol efflux. Filipin III staining confirmed cholesterol retention in gp130-inhibited cells. Ex-vivo investigation on lean PBMCs further defined the impact of gp130 inhibition on the reduction of cholesterol efflux. Our results indicates gp130 is crucial for macrophage reverse cholesterol transport and may be a target for atherosclerosis treatments.

Characteristics of T cell premature senescence in maintenance hemodialysis patients.

Uremia-associated immunodeficiency, mainly characterized by T cell dysfunction, exists in patients on maintenance hemodialysis (MHD) and promotes systemic inflammation. However, T cell senescence, one of the causes of T cell dysfunction, has not been clearly revealed yet. In this cross-sectional research, we aimed to study the manifestation of T cell premature senescence in MHD patients and further investigate the associated clinical factors. 76 MHD patients including 33 patients with cardiovascular diseases (CVD) and 28 patients with arteriovenous fistula (AVF) event history were enrolled in this study. Complementarity determining region 3 (CDR3) of T cell receptor (TCR) was analyzed by immune repertoire sequencing (IR-Seq). CD28- T cell subsets and expression of senescence marker p16 and p21 genes were detected by multicolor flow cytometry and RT-qPCR, respectively. MHD patients had significantly decreased TCR diversity (P < 0.001), increased CDR3 clone proliferation (P = 0.001) and a left-skewed CDR3 length distribution. The proportion of CD4 + CD28- T cells increased in MHD patients (P = 0.014) and showed a negative correlation with TCR diversity (P = 0.001). p16 but not p21 expression in T cells was up-regulated in MHD patients (P = 0.039). Patients with CVD exhibited increased expression of p16 and p21 genes (P = 0.010 and 0.004, respectively), and patients with AVF events showed further TCR diversity and evenness reduction (P = 0.002 and 0.017, respectively) compared to patients without the comorbidities. Moreover, age, average convection volume, total cholesterol, high-density lipoprotein cholesterol and transferrin saturation were associated with TCR diversity or CD4 + CD28- T cell proportion (P < 0.05). MHD patients undergo T cell premature senescence characterized by significant TCR diversity reduction and repertoire skew, as well as accumulation of the CD4 + CD28- subset and up-regulation of p16 gene. Patients with CVD or AVF events show higher level of immunosenescence. Furthermore, T cell senescence in MHD patients is associated with blood cholesterol and uremic toxin retention, suggesting potential intervention strategies in the future.

Inhibition of miR-33a-5p in Macrophage-like Cells In Vitro Promotes apoAI-Mediated Cholesterol Efflux.

Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.

Effect of different vitamin E sources on growth performance, nutrient utilization, anti-oxidant status and carcass characteristics in broiler chicken

This study aimed to compare the efficacy of supplementation with a synthetic (DL-α-tocopherol acetate) or herbal source of vitamin E on performance of broiler chicken during a 35-days feeding trial. Day-old broiler chicks (180) were randomly assigned to one of four treatment groups, each with three replicates. T1 (control) received a basal diet, Group T2 received a basal diet with synthetic vitamin E @ 100 g/quintal of feed, Group T3 received a basal diet with herbal vitamin E @ 100 g/quintal of feed and Group T4 received a basal diet with synthetic vitamin E @ 50 g/ quintal of feed + herbal vitamin E @ 50 g/quintal of feed. Supplementation of herbal vitamin E enhanced growth performance traits (average weight gain, feed intake, feed conversion ratio and economics of broiler production), retention of nutrients (dry matter, nitrogen, and ether extract), haematological parameters (Hb, PCV, and TEC) and serum total cholesterol in broiler chicks. Antioxidant status revealed significant increase in GSH but not SOD and CAT. A marked increase in the antibody titer against Newcastle Disease vaccine was recorded in the herbal vitamin E supplemented group. The carcass quality was statistically similar among different dietary treatments, however, lowest abdominal fat and meat cholesterol were recorded in the group supplemented with herbal vitamin E. The study depicts that dietary supplementation of synthetic or herbal vitamin E and their combination @ 100 g/quintal of feed improved the growth performance, antioxidant status and carcass quality of broiler chickens; and that herbal vitamin E was economical and more effective as compared to the synthetic vitamin E in improving the performance of broiler chickens.

Comparison among the Atherogenic Index of Plasma, Ratios of Lipoproteins, Apolipoproteins and Cholesterol Retention Factor (CRF) inPatients with Metabolic Syndrome

Objective: To evaluate various lipid, lipoprotein and apolipoprotein ratios among participants with and without metabolic syndrome.&#x0D; Study Design: Comparative cross-sectional study.&#x0D; Place and Duration of Study: Naval Hospital, Islamabad Pakistan, from Jan 2019 to Dec 2020.&#x0D; Methodology: We selected 164 patients with metabolic syndrome. Metabolic syndrome was diagnosed as per “NCEP-defined metabolic syndrome criteria”. Insulin resistance was calculated using Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Various apolipoproteins were calculated using the turbidimetric method on Humastar-200 and lipoproteins by direct detergent methods.&#x0D; Results: The differences for Apo-B/Apo-A1 were found to be higher among metabolic syndrome subjects [{Metabolic syndrome (n=83):0.55±0.22} vs {Non-Metabolic syndrome (n=81):0.50±0.29}, p=0.271]. Area Under Curve (AUC) was highest for the atherogenic index of plasma [0.744], followed by both total cholesterol/HDLc [0.641], Cholesterol Retention Factor (CRF) having [0.641], Apo-B/Apo-A1[0.593] and HDLc/LDLc [0.418].&#x0D; Conclusion: Differences between subjects with and without NCEP-defined metabolic syndrome were significant for the atherogenic index of plasma (AIP), HDLc/LDLc, and Cholesterol Retention Factor (CRF).

Desorption of cholesterol from model membranes by β-cyclodextrins: Characterizing plaque fighting compounds via quartz crystal microgravimetry with dissipation monitoring.

Atherosclerosis is induced by low-density lipoprotein cholesterol retention in arterial walls and is identifiable by the presence of atherosclerotic plaques. Supported lipid bilayers (SLBs) are model membrane interfaces that resemble biological cell membranes and can be constructed with various combinations of lipid compositions. Herein, we exploit the solvent-assisted lipid bilayer (SALB) formation method to construct SLB model membranes with varying cholesterol compositions to create a novel lipid-sterol interface atop of biosensors. Cholesterol-laden SLBs are utilized as surfaces where quantitative investigations of various molecules’ cholesterol-fighting competencies can occur. At constant flow, we introduced the cyclodextrins 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and methyl-beta-cyclodextrin (MBCD) atop the membranes of varying cholesterol mol fractions and measured changes in relative areal mass and surface viscosity. Quartz crystal microgravimetry with dissipation monitoring allowed for the collection of these measurements in vitro, overtime. Aggregated experimental desorption data correlates as expected with the relative hydrophobicities and topological polar surface areas of the drug candidates. Data also supports a steady-state kinetic model mechanism for our lipid-cholesterol-drug interface. Overall, our findings demonstrate that MBCD not only removes a distinct quantity of cholesterol greater than that of HPBCD, but MBCD also outperforms the rate constant of cholesterol desorption of HPBCD by a factor of 8.

Mechanisms of the Wnt Pathways as a Potential Target Pathway in Atherosclerosis.

The proteins of the Wnt family are involved in a variety of physiological processes by means of several canonical and noncanonical signaling pathways. Wnt signaling has been recently identified as a major player in atherogenesis. In this review, we summarize the existing knowledge on the influence of various components of the Wnt signaling pathways on the initiation and progression of atherosclerosis and associated conditions. We used the PubMed database to search for recent papers on the involvement of the Wnt pathways in atherosclerosis. We used the combination of "Wnt" and "atherosclerosis" keywords to find the initial papers, and chose papers published after 2018. In the first section of the paper, we describe the general mechanisms of the Wnt signaling pathways and their components. The next section is dedicated to existing studies assessing the implication of Wnt signaling elements in different atherogenic processes, such as cholesterol retention, endothelial dysfunction, vascular inflammation, and atherosclerotic calcification of the vessels. Lastly, various therapeutic strategies based on interference with the Wnt signaling pathways are considered. We also compare the efficacy and availability of the proposed treatment methods. Wnt signaling can be considered a potential target in the treatment and prevention of atherosclerosis. Therefore, in this review, we reviewed evidences showing that wnt signaling is an important signal for developing appropriate treatment strategies for atherosclerosis.

The population at low risk of atherothrombotic disease

Background: There are two approaches to the determination of the population at risk of atherothrombotic disease: the herd approach and the targeted approach. In the former scenario, all people are treated, usually with lifestyle changes, but also with medications at times. In the latter scenario, only those deemed at risk of atherothrombotic disease are treated. The author has always favored the latter approach, but for the target approach to be effective, one must know the population at low risk of atherthrombotic disease. Objectives: The purpose of this manuscript is to demonstrate that the population at low risk of atherothrombotic disease can be readily identified and needless treatment can be avoided. Methods: The author has conducted a chart review of his family practice patients roster and separated out the cohort of those who developed some form of atherothrombtic disease from the general population cohort. Results: The author has shown that three major risk factors for atherothrombotic disease can accurately define the population at low risk of atherothrombotic disease: no use of cigarettes, lack of dyslipidemia, and lack of hypertension. Dyslipidemia is defined in terms of the Cholesterol retention Fraction, defined as the difference between low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, that difference divided by the low-density lipoprotein cholesterol, but also whenever low-density lipoprotein cholesterol exceeds 170mg/dl. Hypertension is defined as a systolic blood pressure of 140mmHG or higher or any blood pressure that is being treated. Additionally, the author has shown that in the absence of these three major risk factors, the presence of diabetes mellitus is not associated with early onset atherothrombotic disease. Conclusions: People who do not manifest the three major risk factors for atherothrombotic disease (cigarette smoking, dyslipidemia, and hypertension)are not at risk of early or middle-age onset atherothrombotic disease. Such people do not require therapy though the high blood sugar levels of uncontrolled diabetes mellitus will require treatment to prevent microvascular disease.

The Effects of Sous Vide, Microwave Cooking, and Stewing on Some Quality Criteria of Goose Meat.

Background: Heat treatment methods including frying (with and without fat or oil), deep frying, oven roasting, grilling, charcoal roasting, broiling, steaming, and microwave cooking promote a cascade of adverse changes in the functional properties of meat, including protein fraction, lipid oxidation, and loss of some vitamins and mineral compounds. The aim of this study was to evaluate the influence of three cooking methods (sous vide (SV), microwave (M) cooking, and stewing (S)) on the basic chemical composition, cholesterol content, energy value, mineral concentration, and retention coefficients in goose meat. Methods: Basic chemical composition and mineral analysis were determined using AOAC methods. Total cholesterol content was established using the HPLC method. Results: Both types of goose meat (without and with skin) and heat treatment had a significant effect on nutrient values, mineral concentration, and retention coefficients. The S meat was characterized by a higher protein content than M and SV meat, and had the lowest fat, protein, and cholesterol retention, among other methods. The M meat had lower total cholesterol content than SV and S meat. There were significant differences in energy value for SV, M, and S meats. The SV meat contained less P, Mg, Fe, Zn, and more Na and K than the M and S samples. The highest values of Zn, Mg, and Fe content and the lowest of K and Ca were recorded in S meat compared with the SV and M samples. The retention coefficients of P, Mg, Na, Ca, and K in S meat were lower than in the SV and M samples. The meat without skin was characterized by a lower energy value, fat content, retention of proteins, and cholesterol, but higher fat retention than skin samples. This meat contained more minerals such as P, Mg, Fe, K, Na, and less Ca than skin meat. Higher retention coefficients were observed for Zn, P, Mg, Ca, and lower were observed for Na, Fe, and K in meat without skin than in samples with skin. Conclusions: From a dietary point of view, the most beneficial were SV muscles without skin. Whereas, taking into account the protein, fat content, and retention coefficients of fat, cholesterol, Zn, and Na, the most optimal form of cooking for meat with skin seems to be stewing. These results may be used by consumers in making dietary choices by taking into account the type of goose meat and kind of heat treatment.

Deleting interleukin-10 from myeloid cells exacerbates atherosclerosis in Apoe-/- mice.

Atherosclerosis is initiated by subendothelial retention of lipoproteins and cholesterol, which triggers a non-resolving inflammatory process that over time leads to plaque progression in the artery wall. Myeloid cells and in particular macrophages are the primary drivers of the inflammatory response and plaque formation. Several immune cells including macrophages, T cells and B cells secrete the anti-inflammatory cytokine IL-10, known to be essential for the atherosclerosis protection. The cellular source of IL-10 in natural atherosclerosis progression is unknown. This study aimed to determine the main IL10-producing cell type in atherosclerosis. To do so, we crossed VertX mice, in which IRES-green fluorescent protein (eGFP) was placed downstream of exon 5 of the Il10 gene, with atherosclerosis-prone Apoe-/- mice. We found that myeloid cells express high levels of IL-10 in VertX Apoe-/- mice in both chow and western-diet fed mice. By single cell RNA sequencing and flow cytometry analysis, we identified resident and inflammatory macrophages in atherosclerotic plaques as the main IL-10 producers. To address whether IL-10 secreted by myeloid cells is essential for the protection, we utilized LyzMCre+Il10fl/fl mice crossed into the Apoe-/- background and confirmed that macrophages were unable to secrete IL-10. Chow and western diet-fed LyzMCre+Il10fl/fl Apoe-/- mice developed significantly larger atherosclerotic plaques as measured by en face morphometry than LyzMCre-Il10 fl/flApoe-/-. Flow cytometry and cytokine measurements suggest that the depletion of IL-10 in myeloid cells increases Th17 cells with elevated CCL2, and TNFα in blood plasma. We conclude that macrophage-derived IL-10 is critical for limiting atherosclerosis in mice.

Distinct responses from triglyceride and cholesterol metabolism in common carp (Cyprinus carpio) upon environmental cadmium exposure

Due to high persistence and bioavailability, Cadmium (Cd) is one of the most prevalent environmental contaminants, posing an elevating threat to the ecosystems. It has been evidenced that high-dose Cd elicits deleterious effects on aquatic organisms, but the potential toxicities of Cd at environmentally relevant concentrations remains underappreciated. In this study, we used common carp to investigate how environmental Cd exposure affects triglyceride (TG) and cholesterol metabolism and underlying mechanisms. The data indicated that Cd resulted in the shift of TG from the liver to blood and the movement of cholesterol in the opposite direction, ultimately giving rise to the storage of crude lipid in liver and muscle, especially hepatic cholesterol retention. Cholesterol, instead of TG, became the principal cause during the progression of hepatic lipid accumulation. Mechanistic investigations at transcriptional and translational levels further substantiated that Cd blocked hepatic biosynthesis of TG and enhanced TG efflux out of the liver and fatty acid β-oxidation, which collectively led to the compromised TG metabolism in the liver and accelerated TG export to the serum. Additionally, strengthened synthesis, retarded export and oxidation of cholesterol detailed the hepatic prominent cholesterol retention. Taken together, our results demonstrated that environmental exposure to Cd perturbed lipid metabolism through triggering distinct responses from hepatic TG and cholesterol homeostasis. These indicated that environmental factors (such as waterborne Cd) could be a potential contributor to the prevalence of non-alcoholic fatty-liver disease in aquaculture and more efforts should be devoted to the ecological risk assessment of pollutants under environmental scenarios.

Soluble CD36 Concentration in Diabetic Hypertensive Patients with Coronary Atherosclerosis.

Atherosclerosis is a chronic condition defined by cholesterol retention and arterial wall inflammation. CD36 is indeed a membrane protein found in the monocyte-macrophage systems and endothelial cells involved in the cellular uptake of oxidized low-density lipoproteins and long-chain fatty acids with a crucial role in the pathophysiology of atherosclerosis. The purpose of this research is to compare the diagnostic usefulness of soluble CD36 (sCD36) to high sensitivity C reactive protein (hs-CRP) in diabetic hypertensive individuals with coronary atherosclerosis and the correlation between these parameters in research groups. One hundred individuals with coronary atherosclerosis were divided into four groups based on diabetes mellitus (DM) and/or hypertension (HTN), with 100 participants with routine angiography serving as a control group. The serum levels of sCD36 and hs-CRP were quantified using a sandwich enzyme-linked immunosorbent assay (ELISA) for sCD36 and a particle-enhanced immune turbidimetric assay for hs-CRP, respectively. A study group's lipid profiles, hematological markers, and clinical aspects were compared. Compared to the control, sCD36 and hs-CRP levels in patients increased considerably (p<0.05). The sCD36 level varied substantially between groups (p<0.05), with the DM-HTN group having the highest sCD36 level among the patient groups. Further, the hs-CRP level indicated a significant difference among patients and controls (p<0.05). CD36 correlated significantly and positively with the following terms BMI, hs-CRP, Total cholesterol and non-HDL-C (p<0.05).

Myeloid cell interleukin-10 is essential for atherosclerosis protection in Apoe−/− mice.

Abstract Atherosclerosis, the disease underlying stroke, myocardial infarction and ischemic heart failure, is initiated by the subendothelial retention of lipoproteins and cholesterol, which then triggers a non-resolving inflammatory process driving plaque progression in the artery wall. Myeloid cells and in particular macrophages are the primary driver of this process. IL10 is a prototypic anti-inflammatory cytokine made by several immune cells such as macrophages. IL10 is also essential for the protection against atherosclerosis. However, it is not known which cells are responsible for the IL10 production mediating protection from atherosclerosis. Here, we crossed the VertX mouse model, in which an IRES-enhanced green fluorescent protein (eGFP) fusion protein was placed downstream of exon 5 of the IL-10 gene, to the atherosclerosis-prone Apoe−/− background. We found that myeloid cells express high levels of IL10 GFP in VertX-Apoe−/− mice. By scRNAseq we found that macrophages especially inflammatory macrophages in plaques are the main producers of IL10 in atherosclerosis. To address whether IL10 secreted by myeloid cells is essential for the protection, we developed a LyzMCreIL-10flox/flox mouse crossed in the Apoe−/− background and confirmed that macrophages were unable to secrete IL-10. We discovered that the LyzMCreIL-10flox/floxApoe−/− mice developed significantly more atherosclerosis than LyzMCreIL-10+/+Apoe−/−, both on chow and lipid-rich diet. Flow cytometry data and cytokine measurements suggest that the depletion of IL-10 in myeloid cells increases Th17 cells with elevated IL-17a, IL-17f and CCL20 in blood plasma. These data underscore the critical roles of macrophage-derived IL-10 in limiting atherosclerosis. Supported by grants NIH HL 115232, 145241, and HL088093.

Original contribution: sleeve gastrectomy reduces soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels in patients with morbid obesity.

Early diagnosis of subclinical cardiovascular disease (CVD) in patients with morbid obesity is important. We investigated the effects of sleeve gastrectomy (SG) on serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), oxidized LDL (oxLDL), and other metabolic and inflammatory parameters associated with atherosclerosis in patients with morbid obesity. Body mass index (BMI) measurements and assays of metabolic and inflammatory markers were taken in patients in an SG surgery group and a healthy control group and compared at baseline and 12months after SG. Correlations with changes in these parameters and variations in sLOX-1 were analyzed. Metabolic and inflammatory marker values in the surgery (n = 20) and control (n = 20) groups were significantly different at baseline (p < 0.001). The majority of surgery group biomarker levels significantly decreased with mean BMI loss (- 11.8 ± 9.0, p < 0.001) at 12months, trending toward control group values. Baseline albumin level as well as percentage reductions in oxLDL and the cholesterol retention fraction (CRF) were found to be significantly correlated with percentage reduction in sLOX-1 at 12 months following SG. Metabolic and inflammatory biomarkers elevated at baseline significantly decreased after SG weight loss. Weight loss induced by SG may limit endothelial damage by reducing levels of oxLDL and LOX-1 as assessed by sLOX-1. These findings suggest that sLOX-1 may function as a marker of atherosclerotic disease states in patients with morbid obesity and that metabolic/bariatric surgery can play a meaningful role in CVD prevention.

Prediction of the Population at Risk of Atherothrombotic Disease: A Three Step Approach

The mainstay of the prevention of atherothrombotic disease (ATD, which is atherosclerotic disease, with emphasis on the thrombosis that so often precipitates the acute ATD event, such as acute myocardial infarction, acute cerebral infarction, aortic aneurysm, etc) is the prediction of the population at risk of ATD. There are many predictive tools, all of which use the same general risk factors, but the one favored by the author is the Bowling Green Study (BGS) graph.. This graph is based on the ATD risk factor constellations of 870 people in Bowling Green, Ohio, the county seat of Wood County, in northwest Ohio. (There is one other patient who has full lipid data and blood pressure data, but whose cigarette smoking status is not known.) The ordinate of the graph is the lipid arm and consists of the Cholesterol Retention Fraction (CRF, defined as [LDL-HDL]/LDL). HDL refers to high-density lipoprotein cholesterol and LDL refers to low-density lipoprotein cholesterol. The abscissa of the graph is the blood pressure arm, represented by the systolic blood pressure (SBP). This graph was initially developed in 1981 (using the LDL:HDL ratio) then modified in 1983 (using the CRF), and, by 1988, the author was able to generate a threshold line, which separated the main stream of ATD patients’ CRF-SBP plots from those of a few outliers. (The threshold line is not a regression line, but rather a divider, based on the principle of the fewest false negatives.) The 1988 threshold line was modified in 2000 to its present location at CRF-SBP loci (0.74, 100) and (0.49, 140). Many of the various ATD risk predictors are complex and difficult to use, whereas the graph is simple to use and based on the risk factor constellations of actual ATD patients, wherein lies its value.

Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol Regulatory Element-Binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy.

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). How cholesterol and its carrier lipoproteins are involved in ASCVD is still under extensive investigation. Satins are thus far the best-proven class of cholesterol-lowering medications to improve the clinical outcomes of ASCVD. Statins specifically inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase of the mevalonate pathway for cholesterol biosynthesis. The widely accepted theory is that statins inhibit the hepatic cholesterol synthesis causing upregulation of hepatocyte low-density lipoprotein (LDL) receptor; receptor-mediated LDL uptake and metabolism in the liver results in reduction of circulating LDL cholesterol, which subsequently reduces vascular deposition and retention of cholesterol or LDL in atherogenesis. Nevertheless, cholesterol biosynthesis is ubiquitous, also in extrahepatic cells including those in vascular wall, under tight regulation by sterol regulatory element-binding protein (SREBP), the master gene transcription factor governing cholesterol biosynthesis. Studies have shown that SREBP can be upregulated in vascular wall subject to injury or stent implantation. SREBP can be activated by proinflammatory and mitogenic factors in vascular cells, leading to hyperactive mevalonate pathway, which promotes vascular cell mobilization, further proinflammatory and mitogenic factor release from vascular cells, and vascular inflammation. In this article, we review the cellular cholesterol homeostasis regulation by SREBP and SREBP-mediated vascular hyperactive cholesterol biosynthesis, we term vascular hypercholesterolism, in the pathogenesis of ASCVD and vasculopathy. SREBP functions as a platform bridging cholesterol, inflammation, and vascular cell mobilization in ASCVD pathogenesis. Targeting vascular hypercholesterolism could open a new avenue in fighting against ASCVD.

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

MiR-25-5p regulates endothelial progenitor cell differentiation in response to shear stress through targeting ABCA1.

The importance of flow shear stress (SS) on the differentiation of endothelial progenitor cells (EPCs) has been demonstrated in various studies. Cholesterol retention and microRNAregulation have been also proposed as relevant factors involved in this process, though evidence regarding their regulatory roles in the differentiation of EPCs is currently lacking. In the present study on high shear stress (HSS)-induced differentiation of EPCs, we investigated the importance of ATP-binding cassette transporter 1 (ABCA1), an important regulator in cholesterol efflux, and miR-25-5p, a potential regulator of endothelial reconstruction. We first revealed an inverse correlation between miR-25-5p and ABCA1 expression levels in EPCs under HSS treatment; their direct interaction was subsequently validated by a dual-luciferase reporter assay. Further studies using flow cytometry and quantitative polymerase chain reaction demonstrated that both miR-25-5p overexpression and ABCA1 inhibition led to elevated levels of specific markers of endothelial cells, with concomitant downregulation of smooth muscle cellmarkers. Finally, knockdown of ABCA1 in EPCs significantly promoted tube formation, which confirmed our conjecture. Our current results suggest that miR-25-5p might regulate the differentiation of EPCs partially through targeting ABCA1, and such a mechanism might account for HSS-induced differentiation of EPCs.

Should We Target Global Risk or Risk Factors?

Recent evidence has shaped the new guidelines for the management of dyslipidemia. The importance of accurate risk estimation, subclinical disease detection, and contemporary dyslipidemia management approaches are discussed in this review. Risk prediction helps determine the intensity of management strategies and identify high-risk patients. To overcome the pitfalls of the current risk prediction systems, incorporating genetic scores, biomarkers, and imaging is being explored. Key initiating event in atherogenesis is low-density lipoprotein cholesterol (LDL-C) retention in the arterial wall. Recent dyslipidemia guidelines agree that LDL-C is the primary target, but management approaches vary. Guidelines are shaped by new studies that show the benefits of high-intensity lipid lowering, especially for patients at very high-risk. Global risk assessment should be performed in all individuals for cardiovascular disease prevention. Main target should be the causal risk factors, particularly LDL-C which is one of the most important modifiable causal factors. Lower LDL-C goals will help prevent further events in very high-risk patients.

Proteoglycan binding as proatherogenic function metric of apoB-containing lipoproteins and chronic kidney graft failure

Lipoprotein-proteoglycan binding is an early key event in atherosclerotic lesion formation and thus conceivably could play a major role in vasculopathy-driven chronic graft failure and cardiovascular mortality in renal transplant recipients. The present study investigated whether lipoprotein-proteoglycan binding susceptibility (LPBS) of apoB-containing lipoproteins and levels of the classical atherosclerosis biomarker LDL-C were associated with cardiovascular mortality (n = 130) and graft failure (n = 73) in 589 renal transplant recipients who were followed up from at least 1 year after transplantation for 9.5 years. At baseline, LPBS was significantly higher in patients who subsequently developed graft failure than in those with a surviving graft (1.68 ± 0.93 vs. 1.46 ± 0.49 nmol/mmol, P = 0.001). Cox regression analysis showed an association between LPBS and chronic graft failure in an age- and sex-adjusted model (hazard ratio: 1.45; 95% CI, 1.14–1.85; P = 0.002), but no association was observed with cardiovascular mortality. LDL-C levels were not associated with graft failure or cardiovascular mortality. This study shows that measurement of cholesterol retention outperformed the traditionally used quantitative parameter of LDL-C levels in predicting graft failure, suggesting a higher relevance of proatherogenic function than the quantity of apoB-containing lipoproteins in chronic kidney graft failure.