Inhibitory effect of trans-tiliroside on very low-density lipoprotein secretion in HepG2 cells and mouse liver.

An acylated flavonol glycoside, trans-tiliroside (1), is found in certain parts of different herbs, including the seeds of Rosa canina (Rosaceae). Previous studies on compound 1 have focused on triglyceride (TG) metabolism, including its anti-obesity and intracellular TG reduction effects. In the present study, the effects of compound 1 on cholesterol (CHO) metabolism were investigated using human hepatocellular carcinoma-derived HepG2 cells and mice. Compound 1 decreased CHO secretion in HepG2 cells, which was enhanced by mevalonate in a concentration-dependent manner and decreased the secretion of apoprotein B (apoB)-100, a marker of very low-density lipoprotein (VLDL). Compound 1 also inhibited the activity of microsomal triglyceride transfer proteins, which mediate VLDL formation from cholesterol and triglycerides in the liver. In vivo, compound 1 inhibited the accumulation of Triton WR-1339-induced TG in the blood of fasted mice and maintained low levels of apoB-100. These results suggest that compound 1 inhibits the secretion of CHO as VLDL from the liver and has the potential for use for the prevention of dyslipidemia.

The Role of Triglyceride-rich Lipoproteins and Their Remnants in Atherosclerotic Cardiovascular Disease.

Atherosclerotic cardiovascular disease (ASCVD) is the world's leading cause of death. ASCVD has multiple mediators that therapeutic interventions target, such as dyslipidaemia, hypertension, diabetes and heightened systemic inflammatory tone, among others. LDL cholesterol is one of the most well-studied and established mediators targeted for primary and secondary prevention of ASCVD. However, despite the strength of evidence supporting LDL cholesterol reduction by multiple management strategies, ASCVD events can still recur, even in patients whose LDL cholesterol has been very aggressively reduced. Hypertriglyceridaemia and elevated levels of triglyceride-rich lipoproteins (TRLs) may be key contributors to ASCVD residual risk. Several observational and genetic epidemiological studies have highlighted the causal role of triglycerides within the TRLs and/or their remnant cholesterol in the development and progression of ASCVD. TRLs consist of intestinally derived chylomicrons and hepatically synthesised very LDL. Lifestyle modification has been considered the first line intervention for managing hypertriglyceridaemia. Multiple novel targeted therapies are in development, and have shown efficacy in the preclinical and clinical phases of study in managing hypertriglyceridaemia and elevated TRLs. This comprehensive review provides an overview of the biology, pathogenicity, epidemiology, and genetics of triglycerides and TRLs, and how they impact the risk for ASCVD. In addition, we provide a summary of currently available and novel emerging triglyceride-lowering therapies in development.

Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19.

Background: Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown. Objectives: To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how in COVID-19 populations Lp(a) and tPA change post infection. Methods: Endogenous tPA enzymatic activity, tPA or Lp(a) concentration were measured in plasma from hospitalized patients with and without COVID-19. The association between plasma tPA and adverse clinical outcomes was assessed. Results: In hospitalized patients with COVID-19, we found lower tPA enzymatic activity and higher plasma Lp(a) than that in non-COVID-19 controls. During hospitalization, Lp(a) increased and tPA activity decreased, which associates with mortality. Among those who survived, Lp(a) decreased and tPA enzymatic activity increased during recovery. In patients with COVID-19, tPA activity is inversely correlated with tPA concentrations, thus, in another larger COVID-19 cohort, we utilized plasma tPA concentration as a surrogate to inversely reflect tPA activity. The tPA concentration was positively associated with death, disease severity, plasma inflammatory, and prothrombotic markers, and with length of hospitalization among those who were discharged. Conclusion: High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19.

Plasminogen Receptors Promote Lipoprotein(a) Uptake by Enhancing Surface Binding and Facilitating Macropinocytosis.

BACKGROUND: High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a). METHODS: Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting. RESULTS: The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis. CONCLUSIONS: These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.

Apoprotein E methylation is correlated with immune microenvironment in hepatocellular carcinoma.

BACKGROUND: We aimed to evaluate the correlation of apoprotein E (APOE) transcription and its methylation with immune microenvironment in HCC patients. MATERIAL AND METHODS: The expression profiles of APOE transcription, APOE methylation, and APOE protein were investigated via comprehensive bioinformatic analyses. After that, the association between the immune activation of HCC and APOE transcription and methylation were analyzed. Finally, the prognostic role and immune correlation of the APOE protein in 92 HCC individuals was determined. RESULTS: Based on data from TCGA, GEO, and ICGC datasets, the APOE mRNA was differentially expressed in HCC tissues compared with normal liver tissues. Further, APOE methylation was down-regulated in HCC tissues compared to normal liver tissues. APOE methylation was negatively correlated with APOE transcription in HCC (r=-0.52, p < 0.0001). Based on APOE methylation, the HCC patients were stratified into hypermethylation and hypomethylation subgroups as they exhibited different immune activation statuses. Further, HCC individuals with APOE hypermethylation had a closer immune correlation than those with hypomethylation. Notably, APOE transcription was associated with weak immune infiltrates and activation. Finally, over-expression of the APOE protein was correlated with better survival outcomes, but not correlated with PD-1 or CTLA4 protein in HCC revealed by immunohistochemistry. CONCLUSION: APOE methylation had a closer correlation with immune cells than APOE mRNA, indicating that APOE methylation might play an important role in immune regulation in HCC.

Macadamia nut effects on cardiometabolic risk factors: a randomised trial.

We sought to examine the effects of daily consumption of macadamia nuts on body weight and composition, plasma lipids and glycaemic parameters in a free-living environment in overweight and obese adults at elevated cardiometabolic risk. Utilising a randomised cross-over design, thirty-five adults with abdominal obesity consumed their usual diet plus macadamia nuts (~15 % of daily calories) for 8 weeks (intervention) and their usual diet without nuts for 8 weeks (control), with a 2-week washout. Body composition was determined by bioelectrical impedance; dietary intake was assessed with 24-h dietary recalls. Consumption of macadamia nuts led to increased total fat and MUFA intake while SFA intake was unaltered. With mixed model regression analysis, no significant changes in mean weight, BMI, waist circumference, percent body fat or glycaemic parameters, and non-significant reductions in plasma total cholesterol of 2⋅1 % (-4⋅3 mg/dl; 95 % CI -14⋅8, 6⋅1) and low-density lipoprotein (LDL-C) of 4 % (-4⋅7 mg/dl; 95 % CI -14⋅3, 4⋅8) were observed. Cholesterol-lowering effects were modified by adiposity: greater lipid lowering occurred in those with overweight v. obesity, and in those with less than the median percent body fat. Daily consumption of macadamia nuts does not lead to gains in weight or body fat under free-living conditions in overweight or obese adults; non-significant cholesterol lowering occurred without altering saturated fat intake of similar magnitude to cholesterol lowering seen with other nuts. Clinical Trial Registry Number and Website: NCT03801837 https://clinicaltrials.gov/ct2/show/NCT03801837?term = macadamia + nut&draw = 2&rank = 1.

Twenty-year prospective cohort study of the association between a Japanese dietary pattern and incident dementia: the NILS-LSA project.

PURPOSE: Evidence has suggested that adherence to a Japanese diet may be beneficial for health. However, its association with incident dementia remains unclear. The aim was to explore this association in older Japanese community-dwellers, taking apoprotein E genotype into consideration. METHODS: A 20-year follow-up cohort study involving 1504 dementia-free older Japanese community-dwellers (aged 65-82 years) living in Aichi Prefecture, Japan, was conducted. Based on a previous study, a 9-component-weighted Japanese Diet Index (wJDI9) score (range - 1 to 12) was calculated using 3-day dietary record data and used as an indicator of adherence to a Japanese diet. Incident dementia was confirmed by the Long-term Care Insurance System certificate, and dementia events occurring within the first 5 years of follow-up were excluded. A multivariate-adjusted Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia, and Laplace regression was used to estimate percentile differences (PDs) and 95% CIs (expressed in months) in age at incident dementia (i.e., dementia-free duration differences), according to tertiles (T1-T3) of wJDI9 scores. RESULTS: The median (IQR) follow-up duration was 11.4 (7.8-15.1) years. During the follow-up period, 225 (15.0%) cases of incident dementia were identified. Because the smallest prevalence of incident dementia was 10.7% for the T3 group of wJDI9 scores, to avoid inaccurately estimating the dementia-free duration of participants in the T3 group, the 11th PDs in age at incident dementia between the T1 and T3 groups of wJDI9 scores were estimated. A higher wJDI9 score was associated with a lower risk of incident dementia and a longer dementia-free duration difference. The multivariate-adjusted HR (95% CI) and 11th PDs (95% CI) in age at incident dementia for participants in the T1 vs. T3 group were 1.00 (reference) vs. 0.58 (0.40, 0.86), and 0 (reference) vs. 36.7 (9.9, 63.4) months, respectively. Each 1-point increase of the wJDI9 score was associated with a 5% lower risk of incident dementia (P value = 0.033) and 3.9 (0.3, 7.6) additional months of dementia-free duration (P value = 0.035). No differences were seen in sex or smoking status (current smoker vs. non-current smoker) at baseline. CONCLUSION: These findings suggest that adherence to a Japanese diet defined by wJDI9 is associated with a lower risk of incident dementia in older Japanese community-dwellers, suggesting the benefit of the Japanese diet for dementia prevention.

Metal-induced structural variability of mononuclear metal-binding sites from a database perspective.

Metalloproteins are ubiquitous in all kingdoms of life. Their role and function are tightly related to the local structure of the metal-binding site. In this regard, the MetalPDB database is an invaluable tool since it stores the 3D structure of metal-binding sites and of their corresponding apo forms. In this work, we exploited MetalPDB to compute extensive statistics over >3000 clusters of mononuclear sites about the rearrangements occurring upon change in metalation state. For each cluster, we matched the holo and apo sites so that it was possible to average the distances between all possible pairs of Cα and donor atoms and thus quantitatively assess structural variations by computing the Δ values (mean apo distance - mean holo distance). For most of the structures the backbone is rigid with little to no rearrangement, while donor atoms experience significant changes of their relative position when the metal is removed. Sodium and potassium sites are an exception to this general observation. This is most likely caused by their preference for coordination by the main-chain oxygen atoms, making the rearrangement of donor atoms superimposable to that of the backbone. Magnesium and calcium show a different behavior, despite their chemical similarity: calcium sites undergo a larger reorganization upon metalation although both metals have similar percentage of backbone oxygen as donor atoms. We ascribe this observation to the structural and energetic factors regulating the selectivity for calcium over magnesium.

Apoprotein L1 risk variants and kidney transplantation: a protocol for systematic review and meta-analysis.

Graft survival after kidney transplantation may be influenced by both donors' and recipients' Apoprotein 1 (APOL1) risk variant status. There are several conflicting reports on screening, eligibility, and inclusion of APOL1 risk variant testing in the Kidney donor risk index. We developed a search strategy that included medical subject headings (MeSH), text words, and entry terms in order to search nine databases. The primary measurable outcome is the recipient's post-transplant graft survival time from APOL1 high-risk variant donors. The secondary outcomes are the proportion of APOL1 high-risk variants in end-stage kidney disease requiring a kidney transplant, the proportion in graft recipients and kidney donors; the effect of APOL1 high-risk variant on donor's kidney function post-kidney donation, recipient kidney allograft survival in APOL1 low and high-risk recipients. Confidence and comprehensive meta-analysis software will be used for the meta-analysis. Methodological, clinical, and statistical heterogeneity will be assessed. Publication bias will be visually assessed using the funnel plot. Results will be presented in forest plots with pooled survival time, standard error, and variance. Sub-group analysis will be performed using moderators such as sociodemographic characteristics, hypertension, HIV status, forms of rejection and other environmental factors. The primary outcome effect size is the standardized mean difference in survival time for APOL1 high risk variants in kidney transplants. The differences in kidney function between donors and recipients before and after transplantation would be examined. The suitability of donors with APOL1 high risk variants will be explored in terms of graft survival time, donor kidney function, and the aforementioned moderators.

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins.

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

Pathways and Mechanisms of Cellular Cholesterol Efflux-Insight From Imaging.

Cholesterol is an essential molecule in cellular membranes, but too much cholesterol can be toxic. Therefore, mammalian cells have developed complex mechanisms to remove excess cholesterol. In this review article, we discuss what is known about such efflux pathways including a discussion of reverse cholesterol transport and formation of high-density lipoprotein, the function of ABC transporters and other sterol efflux proteins, and we highlight their role in human diseases. Attention is paid to the biophysical principles governing efflux of sterols from cells. We also discuss recent evidence for cholesterol efflux by the release of exosomes, microvesicles, and migrasomes. The role of the endo-lysosomal network, lipophagy, and selected lysosomal transporters, such as Niemann Pick type C proteins in cholesterol export from cells is elucidated. Since oxysterols are important regulators of cellular cholesterol efflux, their formation, trafficking, and secretion are described briefly. In addition to discussing results obtained with traditional biochemical methods, focus is on studies that use established and novel bioimaging approaches to obtain insight into cholesterol efflux pathways, including fluorescence and electron microscopy, atomic force microscopy, X-ray tomography as well as mass spectrometry imaging.

Opinion: On the Way towards the New Paradigm of Atherosclerosis.

Atherosclerosis is a multicausal disease characterized by the formation of cholesterol-containing plaque in the pronounced intima nearest to the heart's elastic-type arteries that have high levels of blood circulation. Plaques are formed due to arterial pressure-induced damage to the endothelium in areas of turbulent blood flow. It is found in the majority of the Western population, including young people. This denies the monogenic mechanism of atherogenesis. In 1988, Orekhov et al. and Kawai et al. discovered that the presence of atherogenic (modified, including oxidized ones) LDLs is necessary for atherogenesis. On the basis of our discovery, suggesting that the overloading of enterocytes with lipids could lead to the formation of modified LDLs, we proposed a new hypothesis explaining the main factors of atherogenesis. Indeed, when endothelial cells are damaged and then pass through the G2 phase of their cell cycle they secrete proteins into their basement membrane. This leads to thickening of the basement membrane and increases its affinity to LDL especially for modified ones. When the enterocyte transcytosis pathway is overloaded with fat, very large chylomicrons are formed, which have few sialic acids, circulate in the blood for a long time, undergo oxidation, and can induce the production of autoantibodies. It is the sialic acids that shield the short forks of the polysaccharide chains to which autoantibodies are produced. Here, these data are evaluated from the point of view of our new model.

TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases.

Much effort has been dedicated in the recent decades to find novel protein/enzyme-based therapies for human diseases, the major challenge of such therapies being the intracellular delivery and reaching sub-cellular organelles. One promising approach is the use of cell-penetrating peptides (CPPs) for delivering enzymes/proteins into cells. In this review, we describe the potential therapeutic usages of CPPs (mainly trans-activator of transcription protein, TAT) in enabling the uptake of biologically active proteins/enzymes needed in cases of protein/enzyme deficiency, concentrating on mitochondrial diseases and on the import of enzymes or peptides in order to destroy pathogenic cells, focusing on cancer cells.

Endogenous Cardiotonics: Search and Problems.

Medicinal preparations currently used for the treatment of patients with chronic cardiac failure involve those that reduce the heart load (vasodilators, diuretics, beta-blockers, and angiotensin- converting enzyme (ACE) inhibitors). Cardiotonic drugs with the cAMP-dependent mechanism are unsuitable for long-term administration due to the intensification of metabolic processes and an increase in the oxygen demand of the myocardium and all tissues of the body. For many years, digoxin has remained the only preparation enhancing the efficiency of myocardial performance. The detection of digoxin and ouabain in intact animals has initiated a search for other compounds with cardiotonic activity. The review summarizes current data on the effect exerted on the heart performance by endogenous compounds, from simple, such as NO and CO, to steroids, fatty acids, polypeptides, and proteins. Controversial questions and problems with the introduction of scientific achievements into clinical practice are discussed. The results obtained by the authors and their colleagues after many years of studies on the cardiotropic properties of serum lipoproteins are also reported. The experimentally established cardiotonic activity of apoprotein A-1, which is accompanied by a decrease in the relative consumption of oxygen, maybe of great interest.

[Plasma high density lipoproteins phospholipds as an indirect indicator of their cholesterol efflux capacity - new suspected atherosclerosis risk factor]. / Uroven' fosfolipidov lipoproteinov vysokoi plotnosti plazmy kak kosvennyi pokazatel' ikh kholesterin-aktseptiruiushchei sposobnosti.

High density lipoproteins (HDL) are a unique natural structure, protecting the body from the development of atherosclerotic vascular lesions and cardiovascular diseases due to this ability to remove cholesterol from cells. Plasma HDL level estimated by their cholesterol content, is a common lipid parameter, and its decrease is considered as an established atherosclerosis risk factor. However, a number of studies have shown the absence of positive clinical effects after drug-induced increase in HDL cholesterol. There is increasing evidence that not only HDL concentration, but also HDL properties, considered in this review are important. Many studies showed the decrease of HDL cholesterol efflux capacity in patients with coronary heart diseases and its association with disease severity. Some authors consider a decrease of this HDL capacity as a new additional risk factor of atherosclerosis. The review summarizes existing information on various protein and lipid components of HDL with a primary emphasis on the HDL. Special attention is paid to correlation between the HDL cholesterol efflux capacity and HDL phospholipids and the ratio "phospholipids/free cholesterol". The accumulated information indicates importance of evaluation in the HDL fraction not only in terms of their cholesterol, but also phospholipids. In addition to the traditionally used lipid criteria, this would provide more comprehensive information about the activity of the reverse cholesterol transport process in the body and could contribute to the targeted correction of the detected disorders.

Apo A1/Apo B ratio and acute coronary syndrome among peritoneal dialysis patients.

BACKGROUND: Acute coronary syndrome (ACS) is prevalent in continuous ambulatory peritoneal dialysis (CAPD) patients. However, the association between the apoprotein profile and ACS is not well known. Therefore, we aimed to investigate the relationship between apoproteins and ACS in CAPD patients. METHODS: Eighty-one CAPD patients were included in this retrospective study. The primary endpoint was ACS. Predictors were baseline apoprotein levels, particularly the ratio of apoprotein A1 (Apo A1)/apoprotein B (Apo B). Cox regression was used to determine the relationship between Apo A1/Apo B and ACS. RESULTS: During follow-up, 34 (41.98%) CAPD patients experienced an ACS. ACS patients had higher levels of total cholesterol (p = 0.03), low-density lipoprotein cholesterol (LDL-C) (p = 0.04), C-reactive protein (p = 0.01), and Apo B (p < 0.01). However, hemoglobin (p = 0.01) and Apo A1/Apo B (p < 0.01) were lower in the ACS group than the non-ACS group. Patients with Apo A1/Apo B ≥ 1.105 experienced fewer ACS compared with those with Apo A1/Apo B < 1.105 (33.33% vs. 75.56%, p = 0.03). In Cox regression, Apo A1/Apo B (RR, 0.06; 95% CI, 0.00-0.77; p = 0.03) was independently associated with ACS. CONCLUSIONS: Apo A1/Apo B was strongly associated with ACS and may be considered as a predictor of future ACS in CAPD patients.

Lipoprotein(a) and Familial Hypercholesterolemia: A Short Review Including the Laboratory Viewpoint.

Lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) are risk factors for cardiovascular disease (CVD). Individuals with familial hypercholesterolemia (FH) have a risk for CVD due to a high LDL-C value. Lp(a) also increases the CVD risk in FH individuals; thus, the Lp(a) value should be carefully managed. The LDL-C value may partly include Lp(a)-cholesterol (Lp(a)-C) in the measurement. Based on the LDL-C value, some individuals are likely misclassified as having FH and/or the status of treatment of FH can be monitored. The present review describes about Lp(a) in FH individuals in terms of the measurement issue of Lp(a) and the related management of FH.

Risk of cardiovascular disease with lipoprotein(a) in familial hypercholesterolemia: a review.

INTRODUCTION: Lipoprotein(a) (Lp[a]) is a risk factor of cardiovascular disease (CVD). Familial hypercholesterolemia (FH), which exhibits high low-density lipoprotein cholesterol (LDL-C) levels, is a risk factor of CVD. The relationship of Lp(a) with CVD has been characterized in populations specific to FH. MATERIAL AND METHODS: Studies reporting on the relationship of Lp(a) with CVD among FH subjects via PubMed up to 2020 were reviewed. RESULTS: Eight studies were identified as eligible. In the meta-analyses, a high Lp(a) level was significantly and predictively associated with CVD compared to a low Lp(a) level in 2 cross-sectional studies (odds ratio = 2.57; 95% confidence interval (CI): 1.16-5.73) and 6 cohort studies (risk/hazard ratio = 1.91; 95% CI: 1.50-2.43). The totally integrated relative risk of these studies was 1.97 (95% CI: 1.57-2.46). CONCLUSIONS: FH subjects with high Lp(a) levels can have a high CVD risk, and besides LDL-C, attention should be paid to Lp(a) levels in FH subjects.

Unfolding cytochromes c-b562 and Rd apo b562.

We have analyzed the early stages of unfolding of cytochromes c-b562 (PDB ID: 2BC5) and Rd apo b562 (PDB ID: 1YYJ). Our geometrical approach proceeds from an analysis of the crystal structure reported for each protein. We quantify, residue-by-residue and region-by-region, the spatial and angular changes in the structure as the protein denatures, and quantify differences that result from the seven residues that differ in the two proteins. Using two independent analyses, one based on spatial metrics and the second on angular metrics, we establish the order of unfolding of the five helices in cyt c-b562 and the four helices in the apo protein. For the two helices nearest the N-terminal end of both proteins, the ones in the apo protein unfold first. For the two helices nearest the C-terminal end, the interior helix of the apo protein unfolds first, whereas the terminal helix of the holo protein unfolds first. Excluded-volume effects (repulsive interactions) are minimized in turning regions; the overall range in Δ values is Δ = 36.3 Å3 for cyt c-b562 and Δ = 36.6 Å3 for the apo protein, whereas the span for all 20 amino acids is Δ = 167.7 Å3. As our work indicates that the interior helix of cytochrome c-b562 is the first to fold, we suggest that this helix protects the heme from misligation, consistent with ultrafast folding over a minimally frustrated funneled landscape.