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Atherosclerosis Jan 2021Apolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and...
BACKGROUND AND AIMS
Apolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and physiological functions of apoAII are unclear. We aimed to gain insight into the specific roles of apoAII in lipoprotein metabolism and atherosclerosis using a novel rabbit model.
METHODS
Wild-type (WT) rabbits are naturally deficient in apoAII, thus their HDL contains only apoAI. Using TALEN technology, we replaced the endogenous apoAI in rabbits through knock-in (KI) of human apoAII. The newly generated apoAII KI rabbits were used to study the specific function of apoAII, independent of apoAI.
RESULTS
ApoAII KI rabbits expressed exclusively apoAII without apoAI, as confirmed by RT-PCR and Western blotting. On a standard diet, the KI rabbits exhibited lower plasma triglycerides (TG, 52%, p < 0.01) due to accelerated clearance of TG-rich particles and higher lipoprotein lipase activity than the WT littermates. ApoAII KI rabbits also had higher plasma HDL-C (28%, p < 0.05) and their HDL was rich in apoE, apoAIV, and apoAV. When fed a cholesterol-rich diet for 16 weeks, apoAII KI rabbits were resistant to diet-induced hypertriglyceridemia and developed significantly less aortic atherosclerosis compared to WT rabbits. HDL isolated from rabbits with apoAII KI had similar cholesterol efflux capacity and anti-inflammatory effects as HDL isolated from the WT rabbits.
CONCLUSIONS
ApoAII KI rabbits developed less atherosclerosis than WT rabbits, possibly through increased plasma HDL-C, reduced TG and atherogenic lipoproteins. These results suggest that apoAII may serve as a potential target for the treatment of atherosclerosis.
Topics: Animals; Apolipoprotein A-I; Apolipoprotein A-II; Atherosclerosis; Cholesterol; Humans; Lipoproteins, HDL; Rabbits
PubMed: 33296791
DOI: 10.1016/j.atherosclerosis.2020.11.028 -
Frontiers in Endocrinology 2023Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal...
BACKGROUND
Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive.
OBJECTIVE
This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data.
METHODS
Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots.
RESULTS
The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099).
CONCLUSION
Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Risk Factors; Hypercholesterolemia; Mendelian Randomization Analysis; Hypolipidemic Agents; Triglycerides; Cholesterol, HDL; Apolipoproteins B; Urinary Calculi; Hyperlipoproteinemia Type II; Apolipoproteins A
PubMed: 38107516
DOI: 10.3389/fendo.2023.1301163 -
European Journal of Preventive... Oct 2023To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors.
AIMS
To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors.
METHODS AND RESULTS
Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33) and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), lipoprotein(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10-1.16), and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined.
CONCLUSIONS
A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.
Topics: Humans; Coronary Artery Disease; Apolipoprotein A-I; Cross-Sectional Studies; Self Report; Risk Factors; Hypertension; Triglycerides; Lipoprotein(a)
PubMed: 37011137
DOI: 10.1093/eurjpc/zwad096 -
Journal of the American Heart... Apr 2022Approximately 12% of patients with acute myocardial infarction (AMI) experience a recurrent major adverse cardiovascular event within 1 year of their primary event,... (Review)
Review
Approximately 12% of patients with acute myocardial infarction (AMI) experience a recurrent major adverse cardiovascular event within 1 year of their primary event, with most occurring within the first 90 days. Thus, there is a need for new therapeutic approaches that address this 90-day post-AMI high-risk period. The formation and eventual rupture of atherosclerotic plaque that leads to AMI is elicited by the accumulation of cholesterol within the arterial intima. Cholesterol efflux, a mechanism by which cholesterol is removed from plaque, is predominantly mediated by apolipoprotein A-I, which is rapidly lipidated to form high-density lipoprotein in the circulation and has atheroprotective properties. In this review, we outline how cholesterol efflux dysfunction leads to atherosclerosis and vulnerable plaque formation, including inflammatory cell recruitment, foam cell formation, the development of a lipid/necrotic core, and degradation of the fibrous cap. CSL112, a human plasma-derived apolipoprotein A-I, is in phase 3 of clinical development and aims to reduce the risk of recurrent cardiovascular events in patients with AMI in the first 90 days after the index event by increasing cholesterol efflux. We summarize evidence from preclinical and clinical studies suggesting that restoration of cholesterol efflux by CSL112 can stabilize plaque by several anti-inflammatory/immune-regulatory processes. These effects occur rapidly and could stabilize vulnerable plaques in patients who have recently experienced an AMI, thereby reducing the risk of recurrent major adverse cardiovascular events in the high-risk early post-AMI period.
Topics: Apolipoprotein A-I; Cholesterol; Humans; Lipoproteins, HDL; Myocardial Infarction; Plaque, Atherosclerotic
PubMed: 35411789
DOI: 10.1161/JAHA.121.024754 -
Cells Mar 2021Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide... (Review)
Review
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
Topics: Apolipoprotein A-I; Apolipoproteins; Cardiovascular Diseases; Humans; Peptides
PubMed: 33800446
DOI: 10.3390/cells10030597 -
Atherosclerosis Apr 2020Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I concentrations inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. The aim was to assess the causal role of apoA-I using human genetics.
METHODS
We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations (p < 5 × 10) in 20,370 Finnish participants, and meta-analyzed our data with a previous GWAS of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts.
RESULTS
ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; p = 1.5 × 10) but not with confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98,1.30 per 1-SD higher apoA-I), which was different from the observational association. Similar findings were observed using an independent ABCA1 variant in sensitivity analysis.
CONCLUSIONS
Genetic evidence fails to support a cardioprotective role for apoA-I. This is in line with the cumulative evidence showing that HDL-related phenotypes are unlikely to have a protective role in CAD.
Topics: Humans; Apolipoprotein A-I; Biomarkers; Coronary Artery Disease; Finland; Genetic Predisposition to Disease; Genome-Wide Association Study; Incidence; Mendelian Randomization Analysis; Phenotype; Polymorphism, Single Nucleotide; Prognosis; Protective Factors; Risk Assessment; Risk Factors
PubMed: 32113648
DOI: 10.1016/j.atherosclerosis.2020.02.002 -
Advanced Drug Delivery Reviews 2020High-density lipoprotein (HDL) plays an important role in lipid metabolism and especially contributes to the reverse cholesterol transport pathway. Over recent years it... (Review)
Review
High-density lipoprotein (HDL) plays an important role in lipid metabolism and especially contributes to the reverse cholesterol transport pathway. Over recent years it has become clear that the effect of HDL on immune-modulation is not only dependent on HDL concentration but also and perhaps even more so on HDL function. This review will provide a concise general introduction to HDL followed by an overview of post-translational modifications of HDL and a detailed overview of the role of HDL in inflammatory diseases. The clinical potential of HDL and its main apolipoprotein constituent, apoA-I, is also addressed in this context. Finally, some conclusions and remarks that are important for future HDL-based research and further development of HDL-focused therapies are discussed.
Topics: Animals; Apolipoprotein A-I; Humans; Immune System Diseases; Inflammation; Lipoproteins, HDL; Protein Processing, Post-Translational
PubMed: 33080259
DOI: 10.1016/j.addr.2020.10.006 -
Apolipoprotein Mimetic Peptides: An Emerging Therapy against Diabetic Inflammation and Dyslipidemia.Biomolecules Apr 2021Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous... (Review)
Review
Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol levels are inversely associated with coronary heart disease in humans. The beneficial effect of HDL is due, in part, to apolipoproteins A-I and E, which possess anti-inflammatory properties. The functional quality of HDL, however, may be reduced in the context of diabetes. Thus, raising levels of functional HDL is an important target for reducing inflammation and diabetic complications. Apo A-I possesses eight alpha-helical sequences, most of which form class A amphipathic helical structures. Peptides belonging to this class inhibit atherogenesis in several mouse models. Additional peptides based on structural components of apoE have been shown to mediate a rapid clearance of atherogenic lipoproteins in dyslipidemic mice. In this review, we discuss the efficacy of apolipoprotein mimetic peptides in improving lipoprotein function, reducing inflammation, and reversing insulin resistance and cardiometabolic disease processes in diabetic animals.
Topics: Animals; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins E; Atherosclerosis; Biomimetics; Cardiovascular Diseases; Cholesterol; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Models, Animal; Dyslipidemias; Humans; Inflammation; Mice; Peptides
PubMed: 33922449
DOI: 10.3390/biom11050627 -
Nature May 2024Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL)...
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K7-8. We identify compounds that bind to apo(a) K7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).
Topics: Animals; Female; Humans; Male; Mice; Administration, Oral; Drug Discovery; Kringles; Lipoprotein(a); Macaca fascicularis; Mice, Transgenic; Small Molecule Libraries; Plasminogen; Species Specificity; Clinical Trials, Phase II as Topic; Apolipoproteins A
PubMed: 38720069
DOI: 10.1038/s41586-024-07387-z -
Current Opinion in Lipidology Aug 2022A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or... (Review)
Review
PURPOSE OF REVIEW
A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or posttranslational modifications (PTMs) in specific locations on the amino acid backbone. Apolipoproteins A1 and A2 are highly abundant apolipoproteins that mediate HDL structure and function. ApoA1 and apoA2 are known to undergo PTMs, which results in multiple proteoforms. However, the catalogue of apoA1 and apoA2 proteoforms as well as their associations with cardiometabolic health characteristics has not been described until recently. In this brief review, we discuss recent efforts to catalogue the spectrum of apoA1 and apoA2 proteoforms, to understand the relationships between the relative abundance of these proteoforms with cardiometabolic phenotypic characteristics, and we will discuss the implications of these findings to future research.
RECENT FINDINGS
A broad spectrum of apoA1 and apoA2 proteoforms has been characterized. Although, the types of apoA1 and A2 proteoforms are consistent across individuals, the relative abundances of proteoforms can vary substantially between individuals. Proteoform-specific associations with cardiometabolic characteristics in humans, independent of absolute apolipoprotein abundance, have been described. These recent findings suggest multiple levels of protein structural variation that arise from known and unknown metabolic pathways may be important markers or mediators of cardiometabolic health.
SUMMARY
Understanding the associations between apolipoprotein proteoforms and phenotype may lead to enhanced understanding of how apolipoproteins mediate lipid metabolism and affect atherosclerotic cardiovascular disease (ASCVD) risk, which may lead to discovery of novel markers of risk and/or key mechanistic insights that may drive further druggable targets for modifying lipid metabolism and reducing ASCVD risk.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Atherosclerosis; Humans; Protein Processing, Post-Translational
PubMed: 36082946
DOI: 10.1097/MOL.0000000000000840