-
Atherosclerosis May 2022Lipoprotein(a) [Lp(a)] has been established as an independent and causal risk factor for cardiovascular disease. Individuals with elevated levels of Lp(a) (>125 nmol/L;... (Review)
Review
Lipoprotein(a) [Lp(a)] has been established as an independent and causal risk factor for cardiovascular disease. Individuals with elevated levels of Lp(a) (>125 nmol/L; >50 mg/dl) display increased arterial wall inflammation characterized by activation of the endothelium by Lp(a)-carried oxidized phospholipids and recruitment of circulating monocytes. This results in increased secretion of chemoattractants and cytokines, upregulation of adhesion molecules and increased migration of leukocytes through the vessel wall. In addition, Lp(a) is also pivotal in the initiation phase of aortic valve stenosis. The oxidized phospholipids associated, in part, with the apolipoprotein(a) [apo(a)] moiety of Lp(a) stimulate the aortic valve residential cell, the valve interstitial cells (VICs), to either induce osteoblastic differentiation or apoptosis, thereby initiating the process of aortic valve calcification. Lastly, Lp(a) has been linked to systemic inflammation, including the acute phase response. Specifically, the cytokine interleukin 6 (IL-6) has a unique relationship with Lp(a), since the LPA gene contains IL-6 response elements. In this review, we will discuss the pathways and cell types affected by Lp(a) in the context of atherosclerosis, aortic valve stenosis and the acute phase response, highlighting the role of Lp(a) as an inflammatory mastermind.
Topics: Acute-Phase Reaction; Aortic Valve Stenosis; Apolipoproteins A; Apoprotein(a); Humans; Inflammation; Interleukin-6; Lipoprotein(a); Phospholipids; Risk Factors
PubMed: 35606070
DOI: 10.1016/j.atherosclerosis.2022.04.004 -
International Journal of Molecular... Mar 2024Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk... (Review)
Review
Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.
Topics: Humans; Lipoprotein(a); Cardiovascular Diseases; Atherosclerosis; Risk Factors; Apoprotein(a); Apolipoproteins A
PubMed: 38542510
DOI: 10.3390/ijms25063537 -
Atherosclerosis May 2022Lipoprotein(a) [Lp(a)] became besides LDL cholesterol one of the most attractive targets for intervention in cardiovascular disease. Strong genetic evidence supports the... (Review)
Review
Lipoprotein(a) [Lp(a)] became besides LDL cholesterol one of the most attractive targets for intervention in cardiovascular disease. Strong genetic evidence supports the causal association between high Lp(a) concentrations and cardiovascular outcomes. Since specific Lp(a)-lowering therapies are under clinical investigation, the interest in measuring Lp(a) has markedly increased. However, the special structure of the lead protein component of Lp(a), named apolipoprotein(a), creates difficulties for an accurate measurement of Lp(a). A highly homologous repetitive structure, called kringle IV repeat with up to more the 40 repeats, causes a highly polymorphic protein. Antibodies raised against apolipoprotein(a) are mostly directed against the repetitive structure of this protein, which complicates the measurement of Lp(a) in molar terms. Both measurements in mass (mg/dL) and molar terms (nmol/L) are described and a conversion from one into the another unit is only approximately possible. Working groups for standardization of Lp(a) measurements are going to prepare widely available and improved reference materials, which will be a major step for the measurement of Lp(a). This review discusses many aspects of the difficulties in measuring Lp(a). It tries to distinguish between academic and practical concerns and warns to make a mountain out of a molehill, which does no longer allow to see the patient behind that mountain by simply staring at the laboratory issues. On the other hand, the calibration of some assays raises major concerns, which are anything else but a molehill. This should be kept in mind and we should start measuring Lp(a) with the aim of a better risk stratification for the patient and to identify those patients who might be in urgent need for a specific Lp(a)-lowering therapy as soon as it becomes available.
Topics: Apolipoproteins A; Apoprotein(a); Cardiovascular Diseases; Cholesterol, LDL; Humans; Lipoprotein(a)
PubMed: 35606072
DOI: 10.1016/j.atherosclerosis.2022.04.008 -
International Journal of Molecular... Jul 2023Target biomarkers for H at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed....
Target biomarkers for H at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed. At the same time, functional pathway analysis helped identify functional pathways at the protein level. Then, bioinformatics on mRNA sequencing data were conducted between sepsis and normal mouse models. Differential expressional genes with the closest relationship to disease status and development were identified through module correlation analysis. Then, common biomarkers in proteomics and transcriptomics were extracted as target biomarkers. Through analyzing expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS), colocalization analysis on Apoa2 and sepsis phenotype was conducted by summary-data-based Mendelian randomization (SMR). Then, two-sample and drug-target, syndrome Mendelian randomization (MR) analyses were all conducted using the Twosample R package. For protein level, protein quantitative trait loci (pQTLs) of the target biomarker were also included in MR. Animal experiments helped validate these results. As a result, Apoa2 protein or mRNA was identified as a target biomarker for H with a protective, causal relationship with sepsis. HDL and type 2 diabetes were proven to possess causal relationships with sepsis. The agitation and inhibition of Apoa2 were indicated to influence sepsis and related syndromes. In conclusion, we first proposed Apoa2 as a target for H treatment.
Topics: Animals; Mice; Biomarkers; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Hydrogen; Lung Injury; Polymorphism, Single Nucleotide; Proteomics; Sepsis; Apolipoprotein A-II
PubMed: 37511084
DOI: 10.3390/ijms241411325 -
BMC Pregnancy and Childbirth May 2024This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM.
BACKGROUND
This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM.
METHODS
Employing a two-sample Mendelian Randomization (MR) framework, we used Single Nucleotide Polymorphisms (SNPs) as instrumental variables to examine the impact of lipids and apolipoproteins on GDM. The research comprised univariable and multivariable MR analyses, with a prime focus on individual and combined effects of lipid-related traits. Statistical techniques included the fixed-effect inverse variance weighted (IVW) method and supplementary methods such as MR-Egger for comprehensive assessment.
RESULTS
Our findings revealed the following significant associations: apoA-I and HDL cholesterol were inversely correlated with GDM risk, while triglycerides showed a positive correlation. In multivariable analysis, apoA-I consistently exhibited a strong causal link with GDM, even after adjusting for other lipids and Body Mass Index (BMI).
CONCLUSION
The study demonstrates a significant causal relationship between apoA-I and GDM risk.
Topics: Humans; Mendelian Randomization Analysis; Female; Pregnancy; Diabetes, Gestational; Polymorphism, Single Nucleotide; Triglycerides; Apolipoprotein A-I; Cholesterol, HDL; Apolipoproteins; Body Mass Index; Lipids; Risk Factors
PubMed: 38711000
DOI: 10.1186/s12884-024-06556-2 -
Current Hypertension Reports Oct 2022Kidney disease is a strong modulator of the composition and metabolism of the intestinal microbiome that produces toxins and inflammatory factors. The primary pathways... (Review)
Review
PURPOSE OF REVIEW
Kidney disease is a strong modulator of the composition and metabolism of the intestinal microbiome that produces toxins and inflammatory factors. The primary pathways for these harmful factors are blood vessels and nerves. Although lymphatic vessels are responsible for clearance of interstitial fluids, macromolecules, and cells, little is known about whether and how kidney injury impacts the intestinal lymphatic network.
RECENT FINDINGS
Kidney injury stimulates intestinal lymphangiogenesis, activates lymphatic endothelial cells, and increases mesenteric lymph flow. The mesenteric lymph of kidney-injured animals contains increased levels of cytokines, immune cells, isolevuglandin (IsoLG), a highly reactive dicarbonyl, and of apolipoprotein AI (apoAI). IsoLG is increased in the ileum of kidney injured animals, and intestinal epithelial cells exposed to myeloperoxidase produce more IsoLG. IsoLG-modified apoAI directly increases lymphatic vessel contractions and activates lymphatic endothelial cells. Inhibition of IsoLG by carbonyl scavenger treatment reduces intestinal lymphangiogenesis in kidney-injured animals. Research from our group and others suggests a novel mediator (IsoLG-modified apoAI) and a new pathway (intestinal lymphatic network) in the cross talk between kidneys and intestines and heart. Kidney injury activates intestinal lymphangiogenesis and increases lymphatic flow via mechanisms involving intestinally generated IsoLG. The data identify a new pathway in the kidney gut-heart axis and present a new target for kidney disease-induced intestinal disruptions that may lessen the major adverse consequence of kidney impairment, namely cardiovascular disease.
Topics: Animals; Apolipoprotein A-I; Cardiovascular Diseases; Cytokines; Endothelial Cells; Humans; Hypertension; Inflammation; Lymphatic Vessels; Peroxidase; Renal Insufficiency, Chronic
PubMed: 35727522
DOI: 10.1007/s11906-022-01206-4 -
Current Opinion in Lipidology Jun 2021Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The... (Review)
Review
PURPOSE OF REVIEW
Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The majority of the population expresses two apo(a) isoforms, when bound to apoB100 they create two circulating Lp(a) particles. Lp(a) levels are genetically determined and epidemiological studies have established elevated levels of Lp(a) to be a causal risk factor of cardiovascular disease (CVD). Lp(a) levels differ across racial groups and Blacks of Sub-Saharan decent have higher levels when compared to white. In comparison to white populations, studies in minorities are less represented in the published literature. Additionally, there is a lack of standardization in the commercial assays used to measured Lp(a) levels, and hence it is difficult to assess risk based on individual Lp(a) levels, but risk seems to occur in the upper percentiles of the population.
RECENT FINDINGS
A recent study using data from the UK biobank highlights the racial differences in Lp(a) levels and the increase risk in CVD amongst all races.
SUMMARY
This review will highlight Lp(a) biology and physiology with a focus on available data from racially diverse cohorts. There is a need to perform studies in diverse populations to understand if they are at higher risk than whites are.
Topics: Apolipoproteins A; Cardiovascular Diseases; Ethnicity; Heart Disease Risk Factors; Humans; Lipoprotein(a); Risk Factors
PubMed: 33900275
DOI: 10.1097/MOL.0000000000000753 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405 -
Circulation Research Feb 2023Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid...
BACKGROUND
Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls).
METHODS
The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a).
RESULTS
Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM.
CONCLUSIONS
Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.
Topics: Humans; Prospective Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Case-Control Studies; Proteomics; Apolipoproteins; Risk Factors; Coronary Disease; Triglycerides; Cholesterol, HDL; Lipoprotein(a); Apolipoproteins B; Apolipoprotein A-I
PubMed: 36691918
DOI: 10.1161/CIRCRESAHA.122.321690 -
International Journal of Molecular... Nov 2023Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still...
Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still remain unclear. We aimed to explore the role of apolipoprotein A1 (APOA1) in the pathophysiology of PE. The expression of APOA1 was elevated in both plasma and placental tissues, as detected by Western blotting, immunohistochemistry, and a qRT-PCR assay. Importantly, we detected the concentration of APOA1 using the ELISA assay in normal control women ( = 30) and women with preeclampsia ( = 29) from a prospective cohort study. The concentration of APOA1 was not significantly altered in plasma during early and mid-term gestation of the PE patients compared to the NP patients; however, it was elevated during late gestation. Additionally, the concentration of APOA1 was positively associated with systolic blood pressure during late gestation. The proliferation and invasion of trophoblast were all increased in HTR8/SVneo cells transfected with siRNA and decreased in HTR8/SVneo cells treated with the recombinant human APOA1 protein (rhAPOA1). Additionally, we used public datasets to investigate the downstream genes of APOA1 and qRT-PCR for validation. Furthermore, we explored the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) in APOA1 by using a luciferase assay, which showed that the promoter was activated by PPARγ. Additionally, the inhibitory effect of rhAPOA1 on the ability of trophoblast invasion and proliferation can be rescued by the PPARγ inhibitor. Our findings suggest the crucial role of APOA1 in PE, which might provide a new strategy for the prevention and treatment of PE.
Topics: Pregnancy; Humans; Female; Placenta; Pre-Eclampsia; Apolipoprotein A-I; PPAR gamma; Prospective Studies; Trophoblasts; Cell Movement; Cell Proliferation
PubMed: 38003549
DOI: 10.3390/ijms242216363