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Atherosclerosis May 2021Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a) thresholds, but the prevalence of LPA genetic variants and their effect on efficacy of these ASOs are not well described.
METHODS
We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a).
RESULTS
The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied.
CONCLUSIONS
In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.
Topics: Apolipoproteins A; Apoprotein(a); Humans; Lipoprotein(a); Prevalence; Protein Isoforms
PubMed: 33872986
DOI: 10.1016/j.atherosclerosis.2021.03.036 -
Journal of Lipid Research Mar 2016Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor... (Review)
Review
Epidemiological, genetic association, and Mendelian randomization studies have provided strong evidence that lipoprotein (a) [Lp(a)] is an independent causal risk factor for CVD, including myocardial infarction, stroke, peripheral arterial disease, and calcific aortic valve stenosis. Lp(a) levels >50 mg/dl are highly prevalent (20% of the general population) and are overrepresented in patients with CVD and aortic stenosis. These data support the notion that Lp(a) should be a target of therapy for CVD event reduction and to reduce progression of aortic stenosis. However, effective therapies to specifically reduce plasma Lp(a) levels are lacking. Recent animal and human studies have shown that Lp(a) can be specifically targeted with second generation antisense oligonucleotides (ASOs) that inhibit apo(a) mRNA translation. In apo(a) transgenic mice, an apo(a) ASO reduced plasma apo(a)/Lp(a) levels and their associated oxidized phospholipid (OxPL) levels by 86 and 93%, respectively. In cynomolgus monkeys, a second generation apo(a) ASO, ISIS-APO(a)Rx, significantly reduced hepatic apo(a) mRNA expression and plasma Lp(a) levels by >80%. Finally, in a phase I study in normal volunteers, ISIS-APO(a)Rx ASO reduced Lp(a) levels and their associated OxPL levels up to 89 and 93%, respectively, with minimal effects on other lipoproteins. ISIS-APO(a)Rx represents the first specific and potent drug in clinical development to lower Lp(a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis.
Topics: Animals; Apolipoproteins A; Clinical Trials as Topic; Humans; Lipoprotein(a); Oligonucleotides, Antisense
PubMed: 26538546
DOI: 10.1194/jlr.R052258 -
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 -
Physiology & Behavior May 2018Cholecystokinin (CCK) and apolipoprotein A-IV (ApoA-IV) are gastrointestinal peptides that play an important role in controlling energy homeostasis. Lymphatic ApoA-IV...
Cholecystokinin (CCK) and apolipoprotein A-IV (ApoA-IV) are gastrointestinal peptides that play an important role in controlling energy homeostasis. Lymphatic ApoA-IV and plasma CCK secretion are mediated via a chylomicron formation-dependent pathway during a dietary lipid infusion. Given their similar roles as satiating proteins, the present study examines how the two peptides interact in their function. Specifically, this study sought to understand how ApoA-IV regulates CCK secretion. For this purpose, Cck gene expression in the small intestines of ApoA-IV knockout (ApoA-IV-KO) and wild-type (WT) mice were compared under an array of feeding conditions. When fed with a chow or high-fat diet (HFD), basal levels of Cck transcripts were significantly reduced in the duodenum of ApoA-IV-KO mice compared to WT mice. Furthermore, after an oral gavage of a lipid mixture, Cck gene expression in the duodenum was significantly reduced in ApoA-IV-KO mice relative to the change seen in WT mice. To determine the mechanism by which ApoA-IV modulates Cck gene expression, STC-1 cells were transfected with predesigned mouse lysophosphatidic acid receptor 5 (LPAR5) small interfering RNA (siRNA) to knockdown Lpar5 gene expression. In this in-vitro study, mouse recombinant ApoA-IV protein increased Cck gene expression in enteroendocrine STC-1 cells and stimulated CCK release from the STC-1 cells. However, the levels of CCK protein and Cck expression were attenuated when Lpar5 was knocked down in the STC-1 cells. Together these observations suggest that dietary lipid-induced ApoA-IV is associated with Cck synthesis in the duodenum and that ApoA-IV protein directly enhances CCK release through the activation of a LPAR5-dependent pathway.
Topics: Animals; Antioxidants; Apolipoproteins A; Cell Line, Transformed; Cholecystokinin; Dietary Fats; Dose-Response Relationship, Drug; Duodenum; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger; Receptors, Lysophosphatidic Acid; Time Factors; Triglycerides
PubMed: 29378187
DOI: 10.1016/j.physbeh.2018.01.019 -
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 -
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 -
FEBS Letters Dec 2016Conformational plasticity and flexibility are key structural features of ApoAI in lipid metabolism. Amyloidogenic single point mutations, associated with incurable... (Review)
Review
Conformational plasticity and flexibility are key structural features of ApoAI in lipid metabolism. Amyloidogenic single point mutations, associated with incurable familial amyloidosis with fibril deposition in peripheral organs, may have a dramatic impact on the structural and functional features of ApoAI. Here, the consistent body of data on ApoAI variants has been reviewed, with the aim of highlighting the hallmarks of the pathology. In accordance with our observations, as well as that of others, we propose a model that accounts for the alteration of the delicate balance between lipid-free/lipid-bound dynamic states which is based on monomer-to-dimer interconversion via domain swapping.
Topics: Amyloidosis; Apolipoprotein A-I; Humans; Lipid Metabolism; Models, Molecular; Mutation
PubMed: 27790714
DOI: 10.1002/1873-3468.12468 -
Proteins Jan 2022Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid...
Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural consequences introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated that among the four amyloidogenic regions described for human apoA-I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA-I. Structural properties of full-length apoA-I models suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Compared to silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha-helix bundle with the concomitant exposure of APR1 to the solvent, suggesting an insight into the early steps involved in its aggregation. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of this region.
Topics: Amino Acid Sequence; Amyloid; Apolipoprotein A-I; Conserved Sequence; Evolution, Molecular; Humans; Molecular Dynamics Simulation; Mutation; Protein Stability; Thermodynamics
PubMed: 34414600
DOI: 10.1002/prot.26217 -
Liver International : Official Journal... Jan 2023Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation...
BACKGROUND AND AIMS
Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown.
METHODS
In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study.
RESULTS
The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury.
CONCLUSIONS
Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.
Topics: Humans; Mice; Animals; NF-kappa B; Apolipoprotein A-I; Pyroptosis; Toll-Like Receptor 4; Signal Transduction; Liver; Liver Diseases; Reperfusion Injury; Macrophages
PubMed: 36203339
DOI: 10.1111/liv.15448