RESUMEN
T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.
Asunto(s)
Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Proproteína Convertasa 9 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Proproteína Convertasa 9/metabolismo , Humanos , Animales , Inmunoterapia/métodos , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Línea Celular Tumoral , Microambiente Tumoral , Inhibidores de PCSK9 , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/metabolismo , MasculinoRESUMEN
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.
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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
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: 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
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
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
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
Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its tissues and organs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme released in response to the drop in cholesterol level occurring in sepsis. Our study aimed to evaluate the prognostic role of serum Proprotein convertase subtilisin/kexin type 9 (PCSK9) level in children with sepsis and severe sepsis. Sixty children were included in this study. They were divided into two groups: 30 children in the sepsis group and 30 in the severe sepsis group. Another 30 apparently healthy children were included as a control group. Blood samples were withdrawn from all included children for complete blood count (CBC), renal function tests (RFT), liver function tests (LFT), LDL-cholesterol (LDL-C), blood culture, and serum PCSK9. In this study, PCSK9 and LDL-C were higher in the two sepsis groups than in the control group (p < 0.05). They were also higher in the severe sepsis group than the sepsis group and in the non-survivors than in the survivors (p < 0.05). PCSK9 was positively correlated with length of hospital stay in surviving children (r = 0.67, p = 0.001) and had predicted significant hematological dysfunction (adjusted B = - 96.95, p = 0.03). In conclusion, the PCSK9 assay can be used as a biomarker for bad prognosis in children suffering from clinical sepsis.
Asunto(s)
Biomarcadores , Proproteína Convertasa 9 , Sepsis , Humanos , Proproteína Convertasa 9/sangre , Sepsis/sangre , Sepsis/diagnóstico , Masculino , Femenino , Niño , Preescolar , Biomarcadores/sangre , Pronóstico , LDL-Colesterol/sangre , Lactante , Estudios de Casos y ControlesRESUMEN
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 µM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.
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Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/inmunología , Células Hep G2 , Inhibidores de PCSK9 , Resonancia por Plasmón de Superficie , Receptores de LDL/metabolismo , Epítopos/inmunología , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/inmunologíaRESUMEN
BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.
Asunto(s)
Cirugía Bariátrica , Obesidad , Inhibidor 1 de Activador Plasminogénico , Proproteína Convertasa 9 , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proproteína Convertasa 9/sangre , Proproteína Convertasa 9/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Obesidad/cirugía , Obesidad/metabolismo , Obesidad/sangre , Estudios Longitudinales , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
INTRODUCTION: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%). METHODS AND ANALYSIS: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period. ETHICS AND DISSEMINATION: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214. DISSEMINATION: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society. TRIAL REGISTRATION NUMBER: ChiCTR2200066675.
Asunto(s)
Síndrome Coronario Agudo , Anticuerpos Monoclonales Humanizados , Enfermedad de la Arteria Coronaria , Inhibidores de PCSK9 , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , LDL-Colesterol/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/diagnóstico por imagen , Femenino , Masculino , Resultado del Tratamiento , Persona de Mediana Edad , Proproteína Convertasa 9RESUMEN
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.
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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
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.
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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
From the Cynanchum wilfordii roots, 32 compounds, including 5 previously undescribed (1, 4-6, 12) and 27 known (2, 3, 7-11, 13-32) compounds, were isolated, and their structures were elucidated using NMR spectroscopic data and MS data aided by ECD calculations or the modified Mosher's reaction. All isolates were tested for their inhibitory effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) secretion. Among the isolates, compound 4, a methyl cholesterol analog, exhibited the most potent effect in reducing PCSK9 secretion, along with PCSK9 downregulation at the mRNA and protein levels via FOXO1/3 upregulation. Moreover, compound 4 attenuated statin-induced PCSK9 expression and enhanced the uptake of DiI-LDL low-density lipoprotein. Thus, compound 4 is suggested to be a potential candidate for controlling cholesterol levels.
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Cynanchum , Inhibidores de PCSK9 , Raíces de Plantas , Proproteína Convertasa 9 , Raíces de Plantas/química , Proproteína Convertasa 9/metabolismo , Cynanchum/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol metabolism and cardiovascular diseases, has recently garnered attention for its emerging involvement in cancer biology. The multifunctional nature of PCSK9 extends beyond lipid regulation and encompasses a wide range of cellular processes that can influence cancer progression. Studies have revealed that PCSK9 can modulate signaling pathways, such as PI3K/Akt, MAPK, and Wnt/ß-catenin, thereby influencing cellular proliferation, survival, and angiogenesis. Additionally, the interplay between PCSK9 and cholesterol homeostasis may impact membrane dynamics and cellular migration, further influencing tumor aggressiveness. The central role of the immune system in monitoring and controlling cancer is increasingly recognized. Recent research has demonstrated the ability of PCSK9 to modulate immune responses through interactions with immune cells and components of the tumor microenvironment. This includes effects on dendritic cell maturation, T cell activation, and cytokine production, suggesting a role in shaping antitumor immune responses. Moreover, the potential influence of PCSK9 on immune checkpoints such as PD1/PD-L1 lends an additional layer of complexity to its immunomodulatory functions. The growing interest in cancer immunotherapy has prompted exploration into the potential of targeting PCSK9 for therapeutic benefits. Preclinical studies have demonstrated synergistic effects between PCSK9 inhibitors and established immunotherapies, offering a novel avenue for combination treatments. The strategic manipulation of PCSK9 to enhance tumor immunity and improve therapeutic outcomes presents an exciting area for further investigations. Understanding the mechanisms by which PCSK9 influences cancer biology and immunity holds promise for the development of novel immunotherapeutic approaches. This review aims to provide a comprehensive analysis of the intricate connections between PCSK9, cancer pathogenesis, tumor immunity, and the potential implications for immunotherapeutic interventions.
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Inmunoterapia , Neoplasias , Proproteína Convertasa 9 , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/patología , Proproteína Convertasa 9/inmunología , Proproteína Convertasa 9/metabolismo , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Animales , Inhibidores de PCSK9RESUMEN
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.
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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
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.
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Enfermedades Neurodegenerativas , Estrés Oxidativo , Inhibidores de PCSK9 , Proproteína Convertasa 9 , Humanos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Proproteína Convertasa 9/metabolismo , Fármacos Neuroprotectores/farmacologíaRESUMEN
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
BACKGROUND: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. METHODS AND RESULTS: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). CONCLUSIONS: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.