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Lipids in Health and Disease Jun 2024The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using...
BACKGROUND
The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence.
METHODS
Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cholesterol transporter 1, apolipoprotein C3, angiopoietin-like 3, and lipoprotein[a]) were used as exposures. AF was used as an outcome. The inverse variance weighted method was applied as the primary method. Summary-data-based Mendelian randomization analyses were performed for further validation using expression quantitative trait loci data. Mediation analyses were conducted to explore the indirect effect of coronary heart disease.
RESULTS
In the European population, MR analyses demonstrated that elevated levels of lipoprotein(a) increased AF risk. Moreover, analyses focusing on drug targets revealed that the genetically proxied target gene LPA, which simulates the effects of drug intervention by reducing lipoprotein(a), exhibited an association with AF risk. This association was validated in independent datasets. There were no consistent and significant associations observed for other traits when analyzed in different datasets. This finding was also corroborated by Summary-data-based Mendelian randomization analyses between LPA and AF. Mediation analyses revealed that coronary heart disease plays a mediating role in this association. However, in the East Asian population, no statistically significant evidence was observed to support these associations.
CONCLUSIONS
This study provided genetic evidence that Lp(a) may be a causal factor for AF and that LPA may represent a promising pharmacological target for preventing AF in the European population.
Topics: Humans; Angiopoietin-Like Protein 3; Atrial Fibrillation; Cholesterol, LDL; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Hydroxymethylglutaryl CoA Reductases; Lipoprotein(a); Membrane Transport Proteins; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Proprotein Convertase 9; Quantitative Trait Loci; Risk Factors; Triglycerides; White People; East Asian People
PubMed: 38851763
DOI: 10.1186/s12944-024-02163-4 -
Clinical and Translational Science Jun 2024Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated... (Review)
Review
Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low-density lipoprotein cholesterol (LDL-C). HoFH primarily results from loss-of-function (LOF) mutations in the LDL receptor (LDLR), reducing LDL-C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL-C; however, many patients with HoFH still fail to reach their target LDL-C levels and many of these lipid-lowering therapies are not indicated for pediatric use. Angiopoietin-like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL-C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low-density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL-C than non-carriers and lower risk of coronary artery disease. Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH.
Topics: Humans; Translational Research, Biomedical; Hyperlipoproteinemia Type II; Angiopoietin-Like Protein 3; Cholesterol, LDL; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Animals; Anticholesteremic Agents; Receptors, LDL
PubMed: 38845393
DOI: 10.1111/cts.13836 -
Diabetes & Vascular Disease Research 2024This study examines whether Angiopoietin Like 8 (ANGPTL8) is linked to cardiometabolic risk factors (CMRFs) in Saudi women with type 2 diabetes (T2DM).
PURPOSE
This study examines whether Angiopoietin Like 8 (ANGPTL8) is linked to cardiometabolic risk factors (CMRFs) in Saudi women with type 2 diabetes (T2DM).
METHODS
Case-control investigation compared 150 women aged 30-60 with T2DM to 140 healthy women of the same age and gender.
RESULTS
ANGPTL8 levels differed significantly between T2DM and non-diabetics. Fasting blood glucose (FBG), insulin resistance (IR), triglycerides (TG), high-sensitivity C-reactive protein (hs-CRP), body mass index (BMI), and atherogenic index (AIP) of plasma all correlated positively with ANGPTL8 concentrations. Insulin levels correlated negatively with ANGPTL8. Multiple linear regression models showed that elevated ANGPTL8 independently predicted higher FBG, hs-CRP, IR, TG, and AIP in T2DM patients.
CONCLUSION
The study found a significant association between ANGPTL8 levels and IR, hs-CRP, TG, AIP, and BMI in women with T2DM. These components are classified as CMRFs and have the potential to contribute to the development of cardiovascular disease (CVD).
Topics: Humans; Diabetes Mellitus, Type 2; Female; Middle Aged; Angiopoietin-like Proteins; Angiopoietin-Like Protein 8; Pilot Projects; Case-Control Studies; Biomarkers; Saudi Arabia; Adult; Insulin Resistance; Blood Glucose; Cardiovascular Diseases; Body Mass Index; Cardiometabolic Risk Factors; C-Reactive Protein; Peptide Hormones; Risk Assessment; Triglycerides; Insulin; Risk Factors
PubMed: 38843864
DOI: 10.1177/14791641241259792 -
Journal of Ethnopharmacology Jun 2024Traditional Chinese herbal medicine Panax japonicus C.A. Meyer has a long history in clinical treatment of rheumatoid arthritis (RA). Total saponins of Panax japonicus...
ETHNOPHARMACOLOGICAL RELEVANCE
Traditional Chinese herbal medicine Panax japonicus C.A. Meyer has a long history in clinical treatment of rheumatoid arthritis (RA). Total saponins of Panax japonicus C.A. Meyer (TSPJs) were extracted from the root of Panax japonicus C.A. Meyer, and its anti-rheumatism mechanism is still unclear.
AIM OF THE STUDY
To investigate whether TSPJs attenuated synovial angiogenesis in RA and explore the potential mechanisms.
MATERIALS AND METHODS
Potential TSPJs targets involving gene function were predicted by network pharmacology related databases. Bioinformatics analysis and molecular docking technology were used to predict the mechanism of TSPJs in the treatment of RA. The predicted results were validated by cell experiments and a collagen-induced arthritis (CIA) mouse model.
RESULTS
Bioinformatics analysis results showed that TSPJs may inhibit RA-related angiogenesis through the hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) pathways. In vitro, different doses of TSPJs showed a good inhibitory effect on the tube formation of EA.hy926 cells. The results of the cellular thermal shift assay indicated that TSPJs can bind to the HIF-1α, VEGFA, and angiopoietin-1 (ANG-1) proteins. In vivo, the administration of TSPJs alleviated the symptoms of CIA mice, including the arthritis index, hind paw thickness, and swollen joint count. The histological results demonstrated that TSPJs inhibited inflammation, angiogenesis, bone damage, and cartilage destruction. Furthermore, TSPJs decreased the number of vessels and the expression level of CD31. The mechanistic results revealed that TSPJs decreased the expression of HIF-1α, VEGFA, and ANG-1 in the serum or synovial tissues of CIA mice.
CONCLUSION
These results suggest that TSPJs effectively inhibit angiogenesis in RA, and the mechanism may be related to inhibiting the HIF-1α/VEGF/ANG-1 axis.
PubMed: 38838922
DOI: 10.1016/j.jep.2024.118422 -
Frontiers in Pharmacology 2024Cardiovascular disease (CVD) poses a significant global health and economic challenge, with atherosclerosis being a primary cause. Over the past 40 years, substantial...
BACKGROUND
Cardiovascular disease (CVD) poses a significant global health and economic challenge, with atherosclerosis being a primary cause. Over the past 40 years, substantial research has been conducted into the prevention and reversal of atherosclerosis, resulting in the development of lipid-lowering agents such as statins and fibrates. Despite the extensive literature and formulation of numerous therapeutic guidelines in this domain, a comprehensive bibliometric analysis of the current research landscape and trends has not been performed. This study aimed to elucidate the evolution and milestones of research into lipid-lowering treatments for coronary heart disease (CHD) in conjunction with hyperlipidemia through bibliometric analysis, offering insights into future directions for treatment strategies.
METHODS
This study examined publications from 1986 to 2023 retrieved from the Web of Science database (Core Collection). Utilizing tools such as VOSviewer, Pajek, and CiteSpace, we analyzed publication and citation numbers, H-indexes, contributions by countries and institutions, authorship, journal sources, and keyword usage to uncover research trajectories and areas of focus.
RESULTS
Our analysis of 587 publications revealed a recent surge in research output, particularly post-2003. The American Journal of Cardiology published the highest number of studies, with 40 articles, whereas Circulation received the highest number of citations (6,266). Key contributors included the United States, Japan, and China, with the United States leading in citation numbers and the H-index. Harvard University and Leiden University emerged as pivotal institutions, and Professors J. Wouter Jukema and Robert P. Giugliano were identified as leading experts. Keyword analysis disclosed five thematic clusters, indicating a shift in research towards new drug combinations and strategies, signaling future research directions.
CONCLUSION
The last 4 decades have seen a notable rise in publications on lipid-lowering therapies for CHD and hyperlipidemia, with the United States retaining world-leading status. The increase in international collaboration aids the shift towards research into innovative lipid-lowering agents and therapeutic approaches. PCSK9 inhibitors and innovative combination therapies, including antisense oligonucleotides and angiopoietin-like protein 3 inhibitors, provide avenues for future research, intending to maximize the safety and efficacy of treatment approaches.
PubMed: 38828451
DOI: 10.3389/fphar.2024.1393333 -
Heliyon Jun 2024Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell...
Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell toxicity and apoptosis. However, its role in influencing chemotherapy resistance in OC remains ambiguous. In this study, we discovered a correlation between reduced ANGPTL3 levels and a less favorable outcome in OC patients using the Kaplan-Meier Plotter database. Lower levels of ANGPTL3 were detected in paclitaxel (PTX)-resistant OC tissues and cell lines via western blotting and immunohistochemistry. To investigate ANGPTL3's effects, we established SKOV3/PTX and 2780/PTX as PTX-resistant OC cell lines by incrementally increasing PTX exposure and then transfecting them with overexpress ANGPTL3 (OE-ANGPTL3) lentivirus. We conducted various assays such as CCK-8, colony formation, Edu staining, flow cytometry, and transwell to investigate the impact of ANGPTL3 on PTX resistance. Additionally, this effect was examined in a mouse subcutaneous xenograft model. Both and experiments demonstrated that ANGPTL3 overexpression mitigated PTX resistance in OC cells by inactivating the PI3K-AKT-mTOR pathway. In summary, our research reveals that ANGPTL3 enhances PTX sensitivity in OC by downregulating the PI3K-AKT-mTOR pathway. The study of this study suggest that ANGPTL3 could serve as a valuable therapeutic target for OC, signifying its clinical relevance in OC management.
PubMed: 38828336
DOI: 10.1016/j.heliyon.2024.e31520 -
Scientific Reports May 2024Marine mammals possess a specific subcutaneous fat layer called blubber that not only insulates and stores energy but also secretes bioactive substances. However, our...
Marine mammals possess a specific subcutaneous fat layer called blubber that not only insulates and stores energy but also secretes bioactive substances. However, our understanding of its role as a secretory organ in cetaceans is incomplete. To exhaustively explore the hormone-like substances produced in dolphin subcutaneous adipose tissue, we performed seasonal blubber biopsies from captive female common bottlenose dolphins (Tursiops truncatus; N = 8, n = 32) and analyzed gene expression via transcriptomics. Analysis of 186 hormone-like substances revealed the expression of 58 substances involved in regulating energy metabolism, tissue growth/differentiation, vascular regulation, immunity, and ion/mineral homeostasis. Adiponectin was the most abundantly expressed gene, followed by angiopoietin protein like 4 and insulin-like growth factor 2. To investigate the endocrine/secretory responses of subcutaneous adipose tissue to the surrounding temperature, we subsequently compared the mean expression levels of the genes during the colder and warmer seasons. In the colder season, molecules associated with appetite suppression, vasodilation, and tissue proliferation were relatively highly expressed. In contrast, warmer seasons enhanced the expression of substances involved in tissue remodeling, immunity, metabolism, and vasoconstriction. These findings suggest that dolphin blubber may function as an active secretory organ involved in the regulation of metabolism, appetite, and tissue reorganization in response to changes in the surrounding environment, providing a basis for elucidating the function of hormone-like substances in group-specific evolved subcutaneous adipose tissue.
Topics: Animals; Bottle-Nosed Dolphin; Subcutaneous Fat; Female; Transcriptome; Gene Expression Profiling; Hormones; Seasons; Energy Metabolism
PubMed: 38822022
DOI: 10.1038/s41598-024-63018-7 -
Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.The Journal of Clinical Investigation May 2024Primary lymphedema (PL), characterized by tissue swelling, fat accumulation and fibrosis, results from defective lymphatic vessels or valves caused by mutations in genes...
Primary lymphedema (PL), characterized by tissue swelling, fat accumulation and fibrosis, results from defective lymphatic vessels or valves caused by mutations in genes involved in development, maturation and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodelling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR-Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2-TIE1 pathway in lymphatic function.
PubMed: 38820174
DOI: 10.1172/JCI173586 -
Brazilian Journal of Medical and... 2024Ulcerative colitis (UC) is a difficult intestinal disease characterized by inflammation, and its mechanism is complex and diverse. Angiopoietin-like protein 2 (ANGPT2)...
Ulcerative colitis (UC) is a difficult intestinal disease characterized by inflammation, and its mechanism is complex and diverse. Angiopoietin-like protein 2 (ANGPT2) plays an important regulatory role in inflammatory diseases. However, the role of ANGPT2 in UC has not been reported so far. After exploring the expression level of ANGPT2 in serum of UC patients, the reaction mechanism of ANGPT2 was investigated in dextran sodium sulfate (DSS)-induced UC mice. After ANGPT2 expression was suppressed, the clinical symptoms and pathological changes of UC mice were detected. Colonic infiltration, oxidative stress, and colonic mucosal barrier in UC mice were evaluated utilizing immunohistochemistry, immunofluorescence, and related kits. Finally, western blot was applied for the estimation of mTOR signaling pathway and NLRP3 inflammasome-related proteins. ANGPT2 silencing improved clinical symptoms and pathological changes, alleviated colonic inflammatory infiltration and oxidative stress, and maintained the colonic mucosal barrier in DSS-induced UC mice. The regulatory effect of ANGPT2 on UC disease might occur by regulating the mTOR signaling pathway and thus affecting autophagy-mediated NLRP3 inflammasome inactivation. ANGPT2 silencing alleviated UC by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway.
Topics: Colitis, Ulcerative; Animals; Signal Transduction; NLR Family, Pyrin Domain-Containing 3 Protein; Autophagy; TOR Serine-Threonine Kinases; Mice; Inflammasomes; Humans; Disease Models, Animal; Male; Angiopoietin-Like Protein 2; Mice, Inbred C57BL; Female; Angiopoietin-2; Dextran Sulfate; Oxidative Stress; Immunohistochemistry; Blotting, Western
PubMed: 38808888
DOI: 10.1590/1414-431X2024e13379 -
Sleep Medicine Jul 2024Obstructive sleep apnea (OSA) is increasingly recognized as a common condition in the general population and causes significant OSA-associated morbidities including...
BACKGROUND
Obstructive sleep apnea (OSA) is increasingly recognized as a common condition in the general population and causes significant OSA-associated morbidities including cardiovascular and cerebrovascular events such as cerebral small vessel disease (CSVD) and stroke.
METHODS
In this study, using sensitive ELISA immunoassays, we measured subset of endothelial/vascular and inflammatory biomarkers as well as neurofilament light chain (NfL), a sensitive marker for neuroaxonal injury, using plasma from OSA patients post-stroke (Acute Cerebral Infarction (ACI), N = 26) to determine their usefulness as potential prognostic markers in disease progression.
RESULTS
Our results showed significantly increased plasma TNFα and NfL concentrations and decreased concentrations of platelet derived growth factor (PDGF-AA) in post-stroke OSA patients with more severe white matter hyperintensities (WMHs). And after separating the patients based on sex, compared to females, male post-stroke OSA patients with severe WMHs have increased circulating levels of inflammatory chemokine CXCL10 and cytokine Interleukin-10 (IL-10) and significantly decreased levels of Angiopoietin-1 (Ang-1) an important protein responsible for endothelial/vascular integrity functions. Importantly, in a subset of newly diagnosed OSA patients (without prior history of stroke), significantly increased plasma CXCL10 levels and decreased plasma Ang-1 levels were also readily observed when compared to healthy controls, indicating possible altered endothelial integrity and ongoing vascular inflammation in these newly diagnosed OSA patients.
CONCLUSIONS
In summary, our study has identified a novel set of plasma biomarkers including PDGF-AA, CXCL10 and Ang-1 for their potential prognostic value for disease outcomes pre- and post-stroke in OSA patients and use as surrogate markers to measure efficacy of treatment modalities.
Topics: Humans; Sleep Apnea, Obstructive; Male; Biomarkers; Female; Middle Aged; Stroke; Aged; Platelet-Derived Growth Factor; Neurofilament Proteins; Tumor Necrosis Factor-alpha; Chemokine CXCL10; Angiopoietin-1; Inflammation; Interleukin-10
PubMed: 38805859
DOI: 10.1016/j.sleep.2024.05.034