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Advances in Experimental Medicine and... 2022A wealth of evidence indicates that high-density lipoprotein assumes the unique antiatherosclerosis and other cardioprotective properties. Based on that, HDL-C has been...
A wealth of evidence indicates that high-density lipoprotein assumes the unique antiatherosclerosis and other cardioprotective properties. Based on that, HDL-C has been considered as a promising therapy target to reduce the cardiovascular diseases. Recombinant HDL (rHDL) and apolipoprotein mimetic peptides emerge in recent years and have great potential in the future. Here we discussed the pleiotropic therapeutic effect of rHDL based on the effects of atherogenic, angiogenesis, platelet, vascular, and Alzheimer's disease. On the other hand, rHDL not only plays the key role as the major protein component of HDL, it is also used as a nanovector in antiatherosclerotic, antitumor, cardiovascular diagnosing and other therapeutic areas. Synthetic apolipoprotein mimetic peptides like apoA-I and and apoE mimetics have undergone clinical assessment, and we have also reviewed the advances of clinical trials and gave an outlook for the therapy of rHDL and mimetic peptides.
Topics: Apolipoprotein A-I; Apolipoproteins; Atherosclerosis; Cardiovascular Diseases; Humans; Lipoproteins, HDL; Peptides
PubMed: 35575930
DOI: 10.1007/978-981-19-1592-5_14 -
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 -
Advances in Experimental Medicine and... 2022Diabetes is a worldwide public health issue, with the number of cases expected to reach 642 million by 2040. Patients with diabetes are at a two- to four-fold increased...
Diabetes is a worldwide public health issue, with the number of cases expected to reach 642 million by 2040. Patients with diabetes are at a two- to four-fold increased risk of developing cardiovascular disease. This chapter focuses on the anti-diabetic and cardioprotective functions of plasma high-density lipoproteins (HDLs). HDLs and the main HDL apolipoprotein, apoA-I, improves pancreatic beta cell function. ApoA-I also improves insulin sensitivity. The development of novel, bifunctional HDL-based interventions are a promising therapeutic option for the treatment of cardiometabolic diseases.
Topics: Apolipoprotein A-I; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Lipoproteins, HDL
PubMed: 35575925
DOI: 10.1007/978-981-19-1592-5_9 -
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 -
QJM : Monthly Journal of the... Jun 2023Previous studies have reported inconsistent results on the association between circulating lipids and lipid-lowering drugs with the risk of epilepsy.
BACKGROUND
Previous studies have reported inconsistent results on the association between circulating lipids and lipid-lowering drugs with the risk of epilepsy.
AIM
To assess whether genetically predicted circulating lipids and lipid-lowering drugs are causally associated with the risk of epilepsy outcome.
METHODS
We performed a two-sample Mendelian randomization (MR) analysis model to genetically predict the causal effects of circulating lipids (apolipoprotein A [APOA], apolipoprotein B [APOB], cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], lipoprotein A and triglycerides) and lipid-lowering drugs (HMG-CoA reductase [HMGCR] and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) on epilepsy. Nine MR analysis methods were conducted to analyze the final results. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (simple mode, weighted mode, simple median, weighted median, penalized weighted median, MR Egger and MR-Egger [bootstrap]) were conducted as the complement to IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis.
RESULTS
The IVW analysis method demonstrated that there is no causal association between circulating lipids (APOA: odds ratio [OR], 0.958, 95% confidence interval (CI), 0.728-1.261, P = 0.760; APOB: OR, 1.092; 95% CI, 0.979-1.219, P = 0.115; cholesterol: OR, 1.210; 95% CI, 0.981-1.494, P = 0.077; HDL-C: OR, 0.964; 95% CI, 0.767-1.212, P = 0.753; LDL-C: OR, 1.100; 95% CI, 0.970-1.248, P = 0.137; lipoprotein A: OR, 1.082; 95% CI, 0.849-1.379, P = 0.528; triglycerides: OR, 1.126; 95% CI, 0.932-1.360, P = 0.221) and lipid-lowering drugs (HMGCR inhibitors: OR, 0.221; 95% CI, 0.006-8.408, P = 0.878; PCSK9 inhibitors: OR, 1.112; 95% CI, 0.215-5.761, P = 0.902) with risk of epilepsy. The other MR analysis methods and further leave-one-out sensitivity analysis confirmed the robustness of final results.
CONCLUSION
This MR study demonstrated that there were no genetically predicted causal relationships between circulating lipids and lipid-lowering drugs with the risk of epilepsy.
Topics: Humans; Proprotein Convertase 9; Cholesterol, LDL; Mendelian Randomization Analysis; Cholesterol; Triglycerides; Cholesterol, HDL; Apolipoproteins A; Apolipoproteins B; Lipoprotein(a); Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 36964718
DOI: 10.1093/qjmed/hcad048 -
Current Protein & Peptide Science 2022Apolipoprotein-mimetic peptides, mimicking the biological properties of apolipoproteins, have shown beneficial properties against various diseases (central and... (Review)
Review
Apolipoprotein-mimetic peptides, mimicking the biological properties of apolipoproteins, have shown beneficial properties against various diseases (central and peripheral diseases) and have emerged as potential candidates for their treatments. Progress has been made from first-generation to second-generation apolipoprotein-mimetic peptides. Understanding these peptides from the first generation to the second generation is discussed in this review. First, we discussed the structural and therapeutic potentials of first-generation apolipoprotein-mimetic peptides. Further, we discussed the development of second-generation apolipoprotein-mimetic peptides, like dual-domain and bihelical peptides the emergence of second-generation apolipoprotein-mimetic peptides as potential candidates in different preclinical and clinical studies has also been emphasized.
Topics: Apolipoprotein A-I; Apolipoproteins; Peptides
PubMed: 36200201
DOI: 10.2174/1389203723666221003122624 -
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 -
Sub-cellular Biochemistry 2020High-density lipoprotein (HDL) and its main protein component apolipoprotein (apo)A-I, play an important role in cholesterol homeostasis. It has been demonstrated that... (Review)
Review
High-density lipoprotein (HDL) and its main protein component apolipoprotein (apo)A-I, play an important role in cholesterol homeostasis. It has been demonstrated that HDLs comprise of a very heterogeneous group of particles, not only regarding size but also composition. HDL's best described function is its role in the reverse cholesterol transport, where lipid-free apoA-I or small HDLs can accept and take up cholesterol from peripheral cells and subsequently transport this to the liver for excretion. However, several other functions have also been described, like anti-oxidant, anti-inflammatory and anti-thrombotic effects. In this article, the general features, synthesis and metabolism of apoA-I and HDLs will be discussed. Additionally, an overview of HDL functions will be given, especially in the context of some major pathologies like cardiovascular disease, cancer and diabetes mellitus. Finally, the therapeutic potential of raising HDL will be discussed, focussing on the difficulties of the past and the promises of the future.
Topics: Apolipoprotein A-I; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus; Humans; Lipoproteins, HDL; Neoplasms
PubMed: 32189309
DOI: 10.1007/978-3-030-41769-7_16 -
Journal of Medical Primatology Dec 2022Owl monkeys (Aotus infulatus) are frequently affected by heart diseases and, as in humans, dyslipidemia is one of the predisposing factors for adverse cardiovascular...
BACKGROUND
Owl monkeys (Aotus infulatus) are frequently affected by heart diseases and, as in humans, dyslipidemia is one of the predisposing factors for adverse cardiovascular events. In view of this, the study of the lipid profile and plasma apolipoproteins can contribute to the clinical management of this neotropical primate species.
METHODS
Lipid profile as well as A-1 and B apolipoprotein values were analyzed in 60 owl monkeys, studying their relationship with body biometry and the presence of cardiac alterations.
RESULTS
Animals suspected of having heart disease did not show significant differences (p < .05) in terms of biometry or in relation to lipid profile and apolipoproteins A-1 and B values; however, higher values of LDL and ApoB and ApoB/ApoA-1 were observed in this group.
CONCLUSIONS
This study is the first to describe the lipid profile and apolipoprotein values in owl monkeys, and further work will be needed to better elucidate the worthiness of LDL, ApoB, and the ApoB/ApoA-1 ratio in this primate species.
Topics: Animals; Aotidae; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins B
PubMed: 35916434
DOI: 10.1111/jmp.12607