RESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF. METHODS: Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods. RESULTS: There was no significant effect of blood lipid traits on IPF risk (all Pï¼0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50-0.99, P = 0.043). Sensitivity analyses showed no evidence of bias. CONCLUSIONS: Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.
Asunto(s)
HDL-Colesterol , LDL-Colesterol , Fibrosis Pulmonar Idiopática , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9 , Triglicéridos , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/sangre , Proproteína Convertasa 9/genética , Triglicéridos/sangre , LDL-Colesterol/sangre , HDL-Colesterol/sangre , Apolipoproteínas B/genética , Apolipoproteínas B/sangre , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Proteínas de Transporte de Membrana/genética , Hipolipemiantes/uso terapéutico , Proteínas Similares a la Angiopoyetina/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas de Transferencia de Ésteres de Colesterol/genética , Polimorfismo de Nucleótido Simple , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Femenino , Lipoproteína Lipasa , Apolipoproteína B-100 , Hidroximetilglutaril-CoA Reductasas , Receptores de LDL , Apolipoproteína C-IIIRESUMEN
Hypercholesterolemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol metabolism by regulating LDL receptor degradation, making it a therapeutic target for mitigating hypercholesterolemia-associated risks. In this context, we aimed to engineer human H ferritin as a scaffold to present 24 copies of a PCSK9-targeting domain. The rationale behind this protein nanoparticle design was to disrupt the PCSK9-LDL receptor interaction, thereby attenuating the PCSK9-mediated impairment of LDL cholesterol clearance. The N-terminal sequence of human H ferritin was engineered to incorporate a 13-amino acid linear peptide (Pep2-8), which was previously identified as the smallest PCSK9 inhibitor. Exploiting the quaternary structure of ferritin, engineered nanoparticles were designed to display 24 copies of the targeting peptide on their surface, enabling a multivalent binding effect. Extensive biochemical characterization confirmed precise control over nanoparticle size and morphology, alongside robust PCSK9-binding affinity (KD in the high picomolar range). Subsequent efficacy assessments employing the HepG2 liver cell line demonstrated the ability of engineered ferritin's ability to disrupt PCSK9-LDL receptor interaction, thereby promoting LDL receptor recycling on cell surfaces and consequently enhancing LDL uptake. Our findings highlight the potential of ferritin-based platforms as versatile tools for targeting PCSK9 in the management of hypercholesterolemia. This study not only contributes to the advancement of ferritin-based therapeutics but also offers valuable insights into novel strategies for treating cardiovascular diseases.
Asunto(s)
LDL-Colesterol , Nanopartículas , Proproteína Convertasa 9 , Receptores de LDL , Humanos , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/química , Proproteína Convertasa 9/genética , Receptores de LDL/metabolismo , Receptores de LDL/química , Nanopartículas/química , LDL-Colesterol/metabolismo , Inhibidores de PCSK9/farmacología , Inhibidores de PCSK9/química , Ferritinas/química , Ferritinas/metabolismo , Unión ProteicaRESUMEN
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the major regulators of low-density lipoprotein receptor (LDLR). Information on role and regulation of PCSK9 in lung is very limited. Our study focuses on understanding the role and regulation of PCSK9 in the lung. PCSK9 levels are higher in Bronchoalveolar lavage fluid (BALF) of smokers with or without chronic obstructive pulmonary diseases (COPD) compared to BALF of nonsmokers. PCSK9-stimulated cells induce proinflammatory cytokines and activation of MAPKp38. PCSK9 transcripts are highly expressed in healthy individuals compared to COPD, pulmonary fibrosis or pulmonary systemic sclerosis. Cigarette smoke extract reduce PCSK9 levels in undifferentiated pulmonary bronchial epithelial cells (PBEC) but induce in differentiated PBEC. PCSK9 inhibition affect biological pathways, induces lipid peroxidation, and higher level of apoptosis in response to staurosporine. Our results suggest that higher levels of PCSK9 in BALF acts as an inflammatory marker. Furthermore, extracellular and intracellular PCSK9 play different roles.
Asunto(s)
Inflamación , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Inflamación/metabolismo , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/genética , Muerte Celular , Metabolismo de los Lípidos , Masculino , Apoptosis , Células Epiteliales/metabolismo , FemeninoRESUMEN
Pyroptosis has been regarded as caspase-1-mediated monocyte death that induces inflammation, showing a critical and detrimental role in the development of cerebral ischemia-reperfusion injury (IRI). MARCH1 is an E3 ubiquitin ligase that exerts potential anti-inflammatory functions. Therefore, the study probed into the significance of MARCH1 in inflammation and pyroptosis elicited by cerebral IRI. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons were established to simulate cerebral IRI in vivo and in vitro. MARCH1 and PCSK9 expression was tested in MCAO/R-operated mice, and their interaction was identified by means of the cycloheximide assay and co-immunoprecipitation. The functional roles of MARCH1 and PCSK9 in cerebral IRI were subsequently determined by examining the neurological function, brain tissue changes, neuronal viability, inflammation, and pyroptosis through ectopic expression and knockdown experiments. PCSK9 expression was increased in the brain tissues of MCAO/R mice, while PCSK9 knockdown reduced brain damage and neurological deficits. Additionally, inflammation and pyroptosis were inhibited in OGD/R-exposed hippocampal neurons upon PCSK9 knockdown, accompanied by LDLR upregulation and NLRP3 inflammasome inactivation. Mechanistic experiments revealed that MARCH1 mediated ubiquitination and degradation of PCSK9, lowering PCSK9 protein expression. Furthermore, it was demonstrated that MARCH1 suppressed inflammation and pyroptosis after cerebral IRI by downregulating PCSK9 both in vivo and in vitro. Taken together, the present study demonstrate the protective effect of MARCH1 against cerebral IRI through PCSK9 downregulation, which might contribute to the discovery of new therapies for improving cerebral IRI.
Asunto(s)
Inflamación , Proproteína Convertasa 9 , Piroptosis , Daño por Reperfusión , Ubiquitina-Proteína Ligasas , Animales , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Piroptosis/genética , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Ratones , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Neuronas/metabolismo , Neuronas/patología , Masculino , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Regulación hacia Abajo , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Hipocampo/metabolismo , Hipocampo/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Observational studies suggest dyslipidemia as an atopic dermatitis (AD) risk factor and posit that lipid-lowering drugs may influence AD risk, but the causal link remains elusive. Mendelian randomization was applied to elucidate the causal role of serum lipids in AD and assess the therapeutic potential of lipid-lowering drug targets. Genetic variants related to serum lipid traits and lipid-lowering drug targets were sourced from the Global Lipid Genetics Consortium GWAS data. Comprehensive AD data were collated from the UK Biobank, FinnGen, and Biobank Japan. Colocalization, Summary-data-based Mendelian Randomization (SMR), and mediation analyses were utilized to validate the results and pinpoint potential mediators. Among assessed targets, only Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) was significantly linked to a reduced AD risk, corroborated across three separate AD cohorts. No association between serum lipid concentrations or other lipid-lowering drug targets and diminished AD risk was observed. Mediation analysis revealed that beta nerve growth factor (b-NGF) might mediate approximately 12.8% of PCSK9's influence on AD susceptibility. Our findings refute dyslipidemia's role in AD pathogenesis. Among explored lipid-lowering drug targets, PCSK9 stands out as a promising therapeutic agent for AD.
Asunto(s)
Dermatitis Atópica , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9 , Humanos , Dermatitis Atópica/genética , Dermatitis Atópica/tratamiento farmacológico , Proproteína Convertasa 9/genética , Lípidos/sangre , Predisposición Genética a la Enfermedad , Hipolipemiantes/uso terapéutico , Dislipidemias/genética , Dislipidemias/tratamiento farmacológico , Femenino , MasculinoRESUMEN
BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations. CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.
Asunto(s)
Hidroximetilglutaril-CoA Reductasas , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9 , Sarcopenia , Humanos , Sarcopenia/genética , Proproteína Convertasa 9/genética , Hidroximetilglutaril-CoA Reductasas/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Proteínas de Transporte de Membrana/genética , Hipolipemiantes/uso terapéutico , Hipolipemiantes/efectos adversos , Proteínas de la Membrana/genética , Masculino , Femenino , Anciano , Fuerza de la ManoRESUMEN
Mendelian randomization (MR) uses genetic variants as instrumental variables (IVs) to investigate causal relationships between traits. Unlike conventional MR, cis-MR focuses on a single genomic region using only cis-SNPs. For example, using cis-pQTLs for a protein as exposure for a disease opens a cost-effective path for drug target discovery. However, few methods effectively handle pleiotropy and linkage disequilibrium (LD) of cis-SNPs. Here, we propose cisMR-cML, a method based on constrained maximum likelihood, robust to IV assumption violations with strong theoretical support. We further clarify the severe but largely neglected consequences of the current practice of modeling marginal, instead of conditional genetic effects, and only using exposure-associated SNPs in cis-MR analysis. Numerical studies demonstrated our method's superiority over other existing methods. In a drug-target analysis for coronary artery disease (CAD), including a proteome-wide application, we identified three potential drug targets, PCSK9, COLEC11 and FGFR1 for CAD.
Asunto(s)
Descubrimiento de Drogas , Desequilibrio de Ligamiento , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Descubrimiento de Drogas/métodos , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Pleiotropía Genética , Estudio de Asociación del Genoma Completo/métodos , Sitios de Carácter Cuantitativo , Funciones de VerosimilitudRESUMEN
There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = - 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative.
Asunto(s)
Nefropatías Diabéticas , Retinopatía Diabética , Estudio de Asociación del Genoma Completo , Hidroximetilglutaril-CoA Reductasas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9 , Humanos , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Retinopatía Diabética/genética , Retinopatía Diabética/tratamiento farmacológico , Hidroximetilglutaril-CoA Reductasas/genética , Proproteína Convertasa 9/genética , Estudios Transversales , Masculino , LDL-Colesterol/sangre , Polimorfismo de Nucleótido Simple , Femenino , Persona de Mediana EdadRESUMEN
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. CONCLUSION: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.
Asunto(s)
Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Osteoporosis , Inhibidores de PCSK9 , Polimorfismo de Nucleótido Simple , Humanos , Osteoporosis/genética , Osteoporosis/inducido químicamente , Osteoporosis/epidemiología , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Hidroximetilglutaril-CoA Reductasas/genéticaRESUMEN
OBJECTIVE: To explore the correlation between asthma risk and genetic variants affecting the expression or function of lipid-lowering drug targets. METHODS: We conducted Mendelian randomization (MR) analyses using variants in several genes associated with lipid-lowering medication targets: HMGCR (statin target), PCSK9 (alirocumab target), NPC1L1 (ezetimibe target), APOB (mipomersen target), ANGPTL3 (evinacumab target), PPARA (fenofibrate target), and APOC3 (volanesorsen target), as well as LDLR and LPL. Our objective was to investigate the relationship between lipid-lowering drugs and asthma through MR. Finally, we assessed the efficacy and stability of the MR analysis using the MR Egger and inverse variance weighted (IVW) methods. RESULTS: The elevated triglyceride (TG) levels associated with the APOC3, and LPL targets were found to increase asthma risk. Conversely, higher LDL-C levels driven by LDLR were found to decrease asthma risk. Additionally, LDL-C levels (driven by APOB, NPC1L1 and HMGCR targets) and TG levels (driven by the LPL target) were associated with improved lung function (FEV1/FVC). LDL-C levels driven by PCSK9 were associated with decreased lung function (FEV1/FVC). CONCLUSION: In conclusion, our findings suggest a likely causal relationship between asthma and lipid-lowering drugs. Moreover, there is compelling evidence indicating that lipid-lowering therapies could play a crucial role in the future management of asthma.
Asunto(s)
Asma , Hipolipemiantes , Análisis de la Aleatorización Mendeliana , Humanos , Asma/genética , Asma/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Hipolipemiantes/farmacología , Proproteína Convertasa 9/genética , Estudios de Asociación Genética , Pulmón/efectos de los fármacos , Pulmón/patología , Lipoproteína Lipasa/genética , Triglicéridos/sangre , Receptores de LDL/genética , Hidroximetilglutaril-CoA Reductasas/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/genética , Apolipoproteína C-III/genética , Apolipoproteínas B/genética , Pruebas de Función Respiratoria , LDL-Colesterol/sangre , Proteínas de Transporte de Membrana , PPAR alfaRESUMEN
The patient was a 54-year-old woman with familial hypercholesterolemia and remarkable Achilles tendon thickening. At 20 years old, the patient had a total cholesterol level of approximately 300 mg/dL. She started receiving rosuvastatin (5 mg/day) for low-density lipoprotein cholesterol (LDL-C) 235 mg/dL at 42 years old, which was increased to 10 mg/day at 54 years old, decreasing her serum LDL-C level to approximately 90 mg/dL. The serum Lp (a) level was 9 mg/dL. A computed tomography coronary angiogram showed no significant stenosis. Next-generation sequencing revealed a frameshift variant in LDL receptor (LDLR) (heterozygous) and a missense variant in proprotein convertase subtilisin/kaxin type 9 (PCSK9) (heterozygous). Continued statin therapy, in addition to low Lp (a) and female sex, can help prevent cardiovascular disease.
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Tendón Calcáneo , Hiperlipoproteinemia Tipo II , Proproteína Convertasa 9 , Receptores de LDL , Humanos , Tendón Calcáneo/diagnóstico por imagen , Tendón Calcáneo/patología , Femenino , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Receptores de LDL/genética , Persona de Mediana Edad , Proproteína Convertasa 9/genética , Rosuvastatina Cálcica/uso terapéutico , Aterosclerosis/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , LDL-Colesterol/sangre , Mutación Missense , Japón , Pueblos del Este de AsiaRESUMEN
PCSK9 has been recognized as an efficient target for hyperlipidemia and related cardiovascular/cerebrovascular diseases. However, PCSK9 inhibitors in the clinic are all biological products, and no small molecules are available yet. In the current work, we discovered that the crude extract of Euphorbia esula (E. esula) promoted LDL uptake in vitro and then obtained 8 new and 12 known jatrophane diterpenoids by activity-guided isolation. After summarized their structure-activity relationship of PCSK9 inhibition, we selected compound 11 (C11) with potent activity and high abundance to investigate its mechanism and in vivo efficacy. Mechanistically, C11 bound with HNF1α to influence its nuclear distribution and subsequently inhibit PCSK9 transcription, thereby enhancing LDLR and promoting LDL uptake. Moreover, C11 demonstrated obvious lipid-lowering activity in HFD mouse model. In conclusion, we first revealed the novel application of E. esula in the discovery of a lipid-lowering candidate and highlighted the potential of C11 in the treatment of hyperlipidemia.
Asunto(s)
Diterpenos , Euphorbia , Proproteína Convertasa 9 , Euphorbia/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Animales , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Humanos , Ratones , Relación Estructura-Actividad , Masculino , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Células Hep G2 , Ratones Endogámicos C57BL , Transcripción Genética/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Inhibidores de PCSK9RESUMEN
This study investigated the effects of far-infrared (FIR) irradiation on low-density lipoprotein cholesterol (LDL-C) uptake by human hepatocellular carcinoma G2 (HepG2) cells via the regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). FIR irradiation for 30 min significantly decreased PCSK9 expression (p < 0.01) in HepG2 cells. FIR irradiation substantially increased the low-density lipoprotein receptor (p < 0.0001) and LDL-C uptake (p < 0.01). Activation of transient receptor potential vanilloid (TRPV) channels mimicked the effects of FIR irradiation, significantly decreasing the protein expression of PCSK9 (p < 0.05). Conversely, inhibition of TRP channels using ruthenium red reversed the reduction in PCSK9 protein expression following FIR irradiation (p < 0.01). The specific activation of TRPV4 using 4α-PDD mimicked the effect of FIR irradiation (p < 0.01), whereas PCSK9 reduction by FIR irradiation was significantly reversed by the inhibition of TRPV4 using RN1734 (p < 0.05). These findings implied that FIR irradiation emitted from a ceramic lamp specifically increased TRPV4 activity. These findings provide insights into a novel therapeutic approach using FIR irradiation for LDL-C regulation and its implications for cardiovascular health.
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LDL-Colesterol , Regulación hacia Abajo , Rayos Infrarrojos , Proproteína Convertasa 9 , Canales Catiónicos TRPV , Humanos , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Células Hep G2 , Canales Catiónicos TRPV/metabolismo , LDL-Colesterol/metabolismo , Regulación hacia Abajo/efectos de la radiaciónRESUMEN
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.
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Fibrilación Atrial , Estudio de Asociación del Genoma Completo , Hidroximetilglutaril-CoA Reductasas , Lipoproteína(a) , Análisis de la Aleatorización Mendeliana , Proproteína Convertasa 9 , Humanos , Proteína 3 Similar a la Angiopoyetina , Fibrilación Atrial/genética , Fibrilación Atrial/tratamiento farmacológico , LDL-Colesterol/sangre , Predisposición Genética a la Enfermedad , Genómica/métodos , Hidroximetilglutaril-CoA Reductasas/genética , Lipoproteína(a)/genética , Lipoproteína(a)/sangre , Proteínas de Transporte de Membrana , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9/genética , Sitios de Carácter Cuantitativo , Factores de Riesgo , Triglicéridos/sangre , Población Blanca/genética , Pueblos del Este de Asia/genéticaRESUMEN
OBJECTIVE: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. METHODS: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. RESULTS: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). CONCLUSIONS: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.
Asunto(s)
HDL-Colesterol , LDL-Colesterol , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Infarto del Miocardio , Polimorfismo de Nucleótido Simple , Triglicéridos , Humanos , Infarto del Miocardio/genética , Infarto del Miocardio/tratamiento farmacológico , LDL-Colesterol/sangre , Triglicéridos/sangre , Masculino , Femenino , HDL-Colesterol/sangre , Persona de Mediana Edad , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana/genética , Proproteína Convertasa 9/genética , Hipolipemiantes/uso terapéutico , Hidroximetilglutaril-CoA Reductasas/genética , AncianoRESUMEN
BACKGROUND: Many studies have focused on the significance of lipid regulatory genes in the pathophysiology of Coronary artery disease (CAD). ApoB XbaI (rs693) and EcoRI (rs1042031) single nucleoid polymorphisms (SNPs) were investigated to detect whether they are risk factors for CAD. Till now, this association remains uncertain. SMARCA4 (rs1122608) SNP has directly related to dyslipidemia. Loss of function mutations (LOF) in PCSK9 result in a reduction in LDL cholesterol and are associated with protection from the development of CAD. METHODS: This study was conducted on 54 CAD patients who were admitted at Internal Medicine Specialized Hospital (Cardiology Department) and 47 healthy controls. Peripheral blood samples were taken from both groups. DNA was extracted from EDTA-blood samples, then PCR- RFLP for ApoB XbaI (rs693) and EcoRI (rs1042031), SMARCA4 (rs1122608) and PCSK9 (rs505151) SNPs was done. RESULTS: No statistically significant difference was found between patients and controls as regard EcoRI SNP. XbaI (rs693) X + X + genotype was significantly higher in control group (P = 0.0355). SMARCA4 (TT, GT + TT) genotypes, and T allele (P < 0.001); PCSK9 AG genotype and G allele (P = 0.027 and 0.032 respectively) were more frequent in CAD patients than controls. CONCLUSION: SMARCA4 (rs1122608) and PCSK9 (rs505151) SNPs are significantly accompanying with the risk of CAD development in the Egyptian population. X + X + genotype appeared to have a protective effect against CAD. However, no observed association between EcoRI (rs1042031) and the risk of CAD development was found.
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Enfermedad de la Arteria Coronaria , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9 , Receptores de LDL , Humanos , Enfermedad de la Arteria Coronaria/genética , Proproteína Convertasa 9/genética , Polimorfismo de Nucleótido Simple/genética , Egipto/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Receptores de LDL/genética , Estudios de Casos y Controles , Apolipoproteínas B/genética , Factores de Riesgo , Anciano , Genotipo , Estudios de Asociación Genética , Adulto , Frecuencia de los Genes/genética , Alelos , Pueblo Norteafricano , Apolipoproteína B-100RESUMEN
Inclisiran sodium (Brand name: LEQVIO® for s.c. injection syringe 300â |mg, hereinafter referred to as inclisiran), a small interfering ribonucleic acid (siRNA) product that targets the mRNA that encodes the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was approved on September 25, 2023 for the indication of "Familial hypercholesterolemia, hypercholesterolemia" in Japan. Inclisiran is conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes. In vitro and in vivo pharmacology studies demonstrated the lowering effects of PCSK9 and LDL-C in hepatocytes and cynomolgus monkeys. It was considered unlikely to cause clinically significant risks due to toxicities arising from complementary binding to non-target RNA sequences (hybridization-dependent off-target effects). Clinical trials conducted globally including Japan in patients with familial hypercholesterolemia and hypercholesterolemia who did not reach the LDL-C target showed that inclisiran sodium 300â |mg dosed at Day 1, Day 90 and then every 6 months demonstrated significant LDL-C reduction and the efficacy sustained long. The majority of patients achieved the guideline recommended LDL-C targets. Inclisiran sodium 300â |mg was well tolerated and there were no specific safety concerns. Therefore, inclisiran is expected to be a new therapeutic option for the patients with familial hypercholesterolemia and hypercholesterolemia.
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LDL-Colesterol , Proproteína Convertasa 9 , ARN Interferente Pequeño , Humanos , LDL-Colesterol/sangre , Animales , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Hipercolesterolemia/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genéticaRESUMEN
ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.