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Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021,

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = −0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = −0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that naringenin possesses lipid-lowering effects; however, the underlying mechanisms, particularly its specific molecular targets, remain uncertain. Methods: Using bioinformatics, three traditional Chinese medicine databases and one human disease database were integrated to establish two naringenin-target-hyperlipidemia modules: naringenin-oxidative stress (OS) and naringenin-lipid metabolism (LM). Data on 1,850 proteins from 1,871 genetic instruments were sourced from seven previous studies. Using Mendelian randomization based on data from the Integrative Epidemiology Unit genome-wide association study (case, n = 5,153; control, n = 344,069), we identified potential drug targets that were subsequently validated in the UK Biobank (396,565 individuals) and FinnGen (412,181 individuals) cohorts. Using molecular docking and molecular dynamics simulation to verify the binding ability of naringenin and causal protein. Results: In plasma, every standard deviation increase in apolipoprotein B (APOB) was associated with an increased risk of hyperlipidemia (odds ratio [OR] = 9.37, 95% confidence interval [CI], 5.12-17.12; P = 3.58e-13; posterior probability of hypothesis 4 [PPH4] = 0.997), and the same was observed for proprotein convertase subtilisin/kexin type 9 (OR = 1.81, 95% CI, 1.51-2.16; P = 6.87e-11; PPH4 = 1) and neurocan (OR = 2.34, 95% CI, 1.82-3.01; P = 4.09e-11; PPH4 = 0.932). The intersection of two modules and Mendelian randomization result identified APOB as a key regulatory target of naringenin in the treatment of hyperlipidemia. The binding energy between naringenin and APOB was determined to be -7.7 kcal/mol. Additionally, protein-protein interactions and protein-disease networks were analyzed to uncover potential connections between proteins and hyperlipidemia. Conclusion: This Mendelian randomization-based combined analysis offers a robust framework for elucidating the pharmacological effects of naringenin and identifying candidate proteins for further investigation in the context of hyperlipidemia treatment. [ABSTRACT FROM AUTHOR]

Background: Acute coronary syndrome continues to be a significant cardiovascular issue. Statins are commonly acknowledged as medications that reduce LDL-C levels and stabilize plaques. Nevertheless, their efficacy is limited. Presently, PCSK9 inhibitors are suggested to be advantageous in patients who are already receiving statin treatment. The study seeks to assess the safety and effectiveness of PCSK9 inhibitors in individuals who have been treated with statins after experiencing acute coronary syndrome (ACS), as well as investigate the impact on the characteristics of coronary plaque. Methods: Articles were identified from PubMed, Cochrane Central Register of Controlled Trials, and ProQuest. Our analysis comprised trials and observational studies that compared the plaque phenotype, lipid profile, and safety outcomes between PCSK9 inhibitors and a control group in patients with acute coronary syndrome who were already being treated with statins. The random-effect model was used to measure the pooled effect, which was presented in terms of mean difference, standardized mean difference, and risk ratio. Results: Acquired 12 studies that fulfilled our criteria. The addition of PCSK9 inhibitors ameliorates the plaque phenotype significantly in terms of percent atheroma volume (P = 0.02), total atheroma volume (P < 0.010), fibrous cap thickness (P < 0.00001), lipid arc (P < 0.00001), quantitative flow ratio (P = 0.003), and diameter of stenosis (P = 0.0003) but not in lipid/lesion length (P = 0.17). The administration of PCSK9 inhibitors led to a considerable improvement in all lipid profiles (P < 0.00001). Regarding safety analysis, there is no substantial disparity in the likelihood of non-serious side events (RR 1.21; P = 0.2), however, a significant reduction in the risk of serious adverse effects (RR 0.77; P = 0.04) in the PCSK9 inhibitor group. Conclusions: The addition of PCSK9 inhibitors compared to statin-only treatment led to a majority of patients experiencing significant benefits in terms of safety and efficacy following ACS. [ABSTRACT FROM AUTHOR]

Acute coronary syndromes (ACSs) represent a significant global health challenge arising from atherosclerotic cardiovascular disease (ASCVD), with elevated low-density lipoprotein cholesterol (LDL-C) levels being a primary contributor. Despite standard statin therapy, individuals with ACS remain at high risk for recurrent cardiovascular events, particularly in the initial post-ACS period. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), such as evolocumab and alirocumab, offer a potential strategy to reduce LDL-C levels further and mitigate this residual risk. This review delves into the molecular mechanisms, effects on cholesterol metabolism, inflammatory modulation, and clinical outcomes associated with early administration of PCSK9 inhibitors following ACS. [ABSTRACT FROM AUTHOR]

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in lipid metabolism. The factors influencing PCSK9 in acute myocardial infarction (AMI) patients have not been fully understood. Objective To investigate the influence factors of PCSK9 among AMI patients. Methods Patients with an admission diagnosis of AMI between 2010 and 2018 were consecutively enrolled in the Department of Cardiology, Peking University First Hospital. Baseline information was collected from patients' current history, past history, and physical examination in the electronic medical record system at admission, and baseline plasma PCSK9 levels were measured. The related factors of PCSK9 were analyzed using univariate and multivariate linear regressions. The LASSO method was employed, the selected variables were subsequently included in the analysis of a multivariate linear regression model. Results 996 AMI patients were consecutively enrolled from 2010 to 2018, and 37 patients with no PCSK9 measurement results due to insufficient volume of retained blood samples were excluded. A total of 959 patients were included in the analysis. The median PCSK9 levels were 543.1 (425.4, 692.1) ng/mL. The multivariate linear regression analysis of non-genetic factors of PCSK9 showed that gender had the greatest effect (standardized regression coefficient was 0.13). Other significant factors related to PCSK9 levels were history of atrial fibrillation (standardized regression coefficient was 0.09), white blood cell count (standardized regression coefficient was 0.07) and uric acid levels (standardized regression coefficient was 0.07) . Conclusion In patients with AMI, gender, history of atrial fibrillation, blood white blood cell count, and uric acid levels were significant independent factors related to plasma PCSK9 levels.

Abstract Background Acute coronary syndrome continues to be a significant cardiovascular issue. Statins are commonly acknowledged as medications that reduce LDL-C levels and stabilize plaques. Nevertheless, their efficacy is limited. Presently, PCSK9 inhibitors are suggested to be advantageous in patients who are already receiving statin treatment. The study seeks to assess the safety and effectiveness of PCSK9 inhibitors in individuals who have been treated with statins after experiencing acute coronary syndrome (ACS), as well as investigate the impact on the characteristics of coronary plaque. Methods Articles were identified from PubMed, Cochrane Central Register of Controlled Trials, and ProQuest. Our analysis comprised trials and observational studies that compared the plaque phenotype, lipid profile, and safety outcomes between PCSK9 inhibitors and a control group in patients with acute coronary syndrome who were already being treated with statins. The random-effect model was used to measure the pooled effect, which was presented in terms of mean difference, standardized mean difference, and risk ratio. Results Acquired 12 studies that fulfilled our criteria. The addition of PCSK9 inhibitors ameliorates the plaque phenotype significantly in terms of percent atheroma volume (P = 0.02), total atheroma volume (P

A decrease in the levels of low-density lipoprotein receptors (LDLRs) leads to the accumulation of LDL cholesterol (LDL-C) in the bloodstream, resulting in hypercholesterolemia and atherosclerotic cardiovascular diseases. Increasing the expression level or inducing the activity of LDLR in hepatocytes can effectively control hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, primarily produced in the liver, promotes the degradation of LDLR. Inhibiting the expression and/or function of PCSK9 can increase the levels of LDLR on the surface of hepatocytes and promote LDL-C clearance from the plasma. Thus, targeting PCSK9 represents a new strategy for developing preventive and therapeutic interventions for hypercholesterolemia. Currently, monoclonal antibodies are used as PCSK9 inhibitors in clinical practice. However, the need for oral and affordable anti-PCSK9 medications limits the perspective of choosing PCSK9 inhibitors for clinical usage. Emerging research reports have demonstrated that natural phytochemicals have efficacy in maintaining cholesterol stability and regulating lipid metabolism. Developing novel natural phytochemical PCSK9 inhibitors can serve as a starting point for developing small-molecule drugs to reduce plasma LDL-C levels in patients. In this review, we summarize the current literature on the critical role of PCSK9 in controlling LDLR degradation and hypercholesterolemia, and we discuss the results of studies attempting to develop PCSK9 inhibitors, with an emphasis on the inhibitory effects of natural phytochemicals on PCSK9. Furthermore, we provide insight into the mechanisms of action by which the reported phytochemicals exert their potential PCSK9 inhibitory effects against hypercholesterolemia.

Abstract Background Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). Methods Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. Results The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9’s functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells’ migration and proliferation. Conclusion Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro.

Abstract 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.

Background: Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). Methods: Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. Results: The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9's functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells' migration and proliferation. Conclusion: Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) comprised of 692 amino acids is the ninth member of protease family. It binds to the low-density lipoprotein receptor(LDLR), leading to elevated levels of circulating low-density lipoprotein cholesterol(LDLC), which can lead to a number of cardiovascular diseases, and among then the relationship with cardiovascular calcification has recently received attention. Cardiovascular calcification is a kind of ectopic mineralisation in the cardiovascular system, which is mainly characterised by the production of mineral deposits in the vascular wall and vascular valves, and its pathogenesis is related to lipoprotein content, platelet activity, matrix vesicle (MV) release and inflammation, through which PCSK9 may be involved in the occurrence of cardiovascular calcification. Therefore, this article reviews the relationship between PCSK9 and cardiovascular calcification, emphasizing the specific role of PCSK9 in affecting cardiovascular calcification through various pathways, assisting in setting up emerging applications of PCSK9 amid vessel biological science and recognize innovative molecular mechanisms for its treatment. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the potential roles of proprotein convertase subtilisin/ kexin type 9 (PCSK9) and apelin in the etiology of fibromyalgia syndrome (FS). Patients and methods: The retrospective study was conducted between May 2022 and February 2023. Fifty-eight female FS patients (mean age: 45.2±9.9 years; range, 25 to 66 years) and 30 age- and body mass index-matched control subjects (mean age: 43.1±9.9 years; range, 26 to 67 years) were included in the study. Apelin and PCSK9 levels of all individuals were measured using appropriate methods. Results: The levels of PCSK9 (173.2±62.2 vs. 75.1±44.1, p<0.001) and apelin (354.6±195.5 vs. 229.0±83.2, p<0.001) were significantly higher in patients with FS compared to the control group. A positive correlation was found between PCSK9 and apelin levels and various measures, including the Fibromyalgia Impact Questionnaire (FIQ), Symptom Severity Scale (SSS), Pittsburgh Sleep Quality Index (PSQI), and Beck Depression Inventory (BDI). Additionally, there was a positive correlation between apelin levels and FIQ, SSS, PSQI, Beck Anxiety Inventory, and BDI scores. The optimal cutoff value for PCSK9 in predicting FS was 110.0 ng/mL, with a sensitivity of 84.5% and specificity of 83.9% (area under the curve [AUC]=0.920, 95% confidence interval [CI]: 0.852-0.987, p<0.001). For apelin, the optimal cutoff value for predicting FS was 258.8 ng/L, with a sensitivity of 63.8% and specificity of 64.5% (AUC=0.732, 95% CI: 0.623–0.840, p<0.001). Conclusion: Our findings suggest that PCSK9 may play a role in FS etiology and potentially contribute to oxidative stress. Increased apelin levels may be a compensatory response to high oxidative stress, possibly leading to hyperalgesia. Both PCSK9 and apelin can be predictive markers for FS. [ABSTRACT FROM AUTHOR]

Curative lung resection remains the key therapeutic strategy for early-stage non–small cell lung cancer (NSCLC). However, a proportion of patients still experience variable outcomes and eventually develop recurrence or die from their disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a deleterious factor that inhibits tumor cells apoptosis and leads to reduction of lymphocyte infiltration. However, there has been no research on the predicted role of PCSK9 as an immunohistochemical biomarker with survival in resectable NSCLC. One hundred sixty-three patients with resectable NSCLC were retrospectively reviewed, and PCSK9 expression of resected NSCLC was analyzed by immunohistochemistry using tissue microarrays. PCSK9 was associated with recurrence (42.1% relapsed in the PCSK9lo group versus 57.9% relapsed in the PCSK9hi group, P = 0.006) and survival status (39.6% dead in PCSK9lo group versus 60.4% dead in PCSK9hi group, P = 0.004) in patients with resectable NSCLC. Moreover, resectable NSCLC patients with higher PCSK9 expression in tumor tissue experienced poorer disease-free survival (median disease-free survival: 10.5 versus 25.2 mo, hazard ratio = 1.620, 95% confidence interval: 1.124-2.334) and overall suvrival (median overall suvrival: 20.0 versus 54.1 mo, hazard ratio = 1.646, 95% confidence interval: 1.101-2.461) compared to those with lower PCSK9 expression. High PCSK9 expression of tumor was correlated with recurrence and worse survival status of resectable NSCLC in our retrospective study, which indicated that PCSK9 in NSCLC may be an immunohistochemical biomarker of poor prognosis for patients with resectable NSCLC. Further large-scale prospective studies are warranted to establish these results. • Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects various tumor cell processes and immune cells infiltration. • Real-world research of PCSK9 was needed in treatment of resectable non–small cell lung cancer (NSCLC). • Retrospective study addresses the predict role of PCSK9 on resectable NSCLC prognosis. • Patients with high expression of PCSK9 in resected NSCLC experience poor overall and disease-free survival. [ABSTRACT FROM AUTHOR]

• Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and cardiovascular events partly due to measurement methods that cannot distinguish between mature (uncleaved) and furin-cleaved forms of PCSK9. • Risk of the cardiovascular events in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile. • PCSK9 levels could not predict future cardiovascular events, even when mature PCSK9 levels were measured in statin-treated patients with stable coronary artery disease. Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events partly due to measurement methods that cannot distinguish between uncleaved and furin-cleaved forms of PCSK9. This is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The primary endpoint was major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In this case-cohort study, serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among 426 participants who developed MACCE (cases) and 1,478 randomly selected participants (sub-cohort). From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of the primary endpoint in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile (hazard ratio [HR] 0.809; 95% confidence intervals [CI], 0.541-1.209). Similarly, the HR for the highest to lowest quartiles of furin-cleaved PCSK9 was 0.948 (95% CI, 0.645-1.392) (P = 0.784). Compared to the lowest quartile, neither serum mature nor furin-cleaved PCSK9 levels predicted MACCE. In a large-scale secondary prevention cohort, serum mature and furin-cleaved PCSK9 levels did not provide useful information for predicting future cardiovascular events in statin-treated patients with stable CAD. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid--based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Methods and results Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was −49.4% (95% CI: −50.4, −48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. Conclusion In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile. Trial Registration number ClinicalTrials.gov identifier: NCT03814187 [ABSTRACT FROM AUTHOR]

Introduction: This study attempted to investigate how proprotein convertase subtilisin/kexin type 9 (PCSK9) influences the stemness of stomach adenocarcinoma (STAD) cells. Methods: CCK-8 and sphere-formation assays were used to detect cell viability and stemness. qRT-PCR and Western blot were used to detect PCSK9 and TEAD4 expression. The binding relationship was verified by dual-luciferase and chromatin immunoprecipitation assays. The effect of TEAD4 activating PCSK9 on the stemness of STAD cells was detected by bioinformatics, BODIPY 493/503, Oil red O, Western blot, and kits. In vivo experiments verified the role of the TEAD4/PCSK9 axis in tumor formation in nude mice. Results: PCSK9 and TEAD4 were highly expressed in STAD. PCSK9 was enriched in the fatty acid metabolism (FAM) pathway. PCSK9 activated the fatty acid metabolism and promoted the proliferation and stemness of STAD cells. TEAD4 as a transcription factor upstream of PCSK9, cell experiments revealed that knockdown of PCSK9 inhibited STAD cell stemness, whereas further addition of fatty acid inhibitors could attenuate the promoting effect on STAD cell stemness brought by STAD overexpression. Rescue experiments showed overexpressed PCSK9 exerted an inhibitory effect on the stemness of STAD cells brought by TEAD4 knockdown. The hypothesis that TEAD4/PCSK9 axis can promote STAD cell growth was confirmed by in vivo experiments. Conclusion: Transcription factor TEAD4 could activate PCSK9 to promote the stemness of STAD cells through FAM. These results added weight to the assumption that TEAD4/PCSK9 axis has the potential to be the therapeutic target that inhibits cancer stem cell in STAD. [ABSTRACT FROM AUTHOR]

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory vascular disease caused by various risk factors, in particular smoking, obesity, high blood pressure, and dyslipidemia. In addition, such signaling pathways as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt, which are associated with the inflammatory response in the human body, are involved in the pathogenesis of atherosclerosis. Therapeutic targeting of inflammatory pathways, especially the NLRP3 inflammasome pathway and the cascade of reactions regulated by it leading to the production of inflammatory interleukin-1β, may represent a new avenue for the treatment of atherosclerotic diseases. This article summarizes knowledge of the cellular participants and key inflammatory signaling pathways in atherosclerosis, discusses preclinical studies targeting these key pathways in atherosclerosis, clinical trials that will target some of these processes, and the effects of suppressing inflammation and atherosclerosis.

Background: Single-nucleotide polymorphisms (SNPs) in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are known to be associated with susceptibility to several cerebrovascular diseases, including ischemic stroke (IS). The aims of this study was to evaluate associations between PCSK9 gene polymorphisms and the risk of IS. Based on previous reports linking PCSK9 SNPs to plasma lipid levels and to atherosclerosis, and to inconsistencies in the reported associations between the SNPs, plasma lipid levels and IS risk, we choose the PCSK9 rs505151, rs529787, and rs17111503 to performe the association analysis. Methods: Using multiple databases, all relevant case-control and cohort studies that matched our search criteria were collected. Quality assessment of included studies was performed using the Newcastle-Ottawa Scale. Demographic and genotype data were extracted from each study, and meta-analysis was performed using Stata/MP 17.0. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed and random effects models. Results: A critical evaluation was conducted on ten case-control studies, involving a total of 2426 cases and 2424 controls. Pooled results from the allelic models indicated the PCSK9 rs505151 G allele (OR: 1.41, 95% CI: 1.06-1.87, p = 0.019, I2 = 53.9%) and the PCSK9 rs17111503 A allele (OR: 1.38, 95% CI: 1.22-1.55, p < 0.001, I2 = 43.5%) were significantly associated with IS. Study qualities ranged from moderate (n = 4) to good (n = 6). Begg's and Egger's tests results indicated there was no evidence of publication bias in the findings (p > 0.05). Conclusions: This meta-analysis demonstrated that G allele variant of PCSK9 rs505151 and A allele variant of PCSK9 rs17111503 were associated with an increased risk of IS. Based on our findings, these SNPs could serve as potential targets for the diagnosis and treatment of IS. The integration of information on genetic polymorphism into IS risk prediction model may be beneficial in routine clinical practice. [ABSTRACT FROM AUTHOR]

Acute coronary syndromes (ACSs) represent a significant global health challenge arising from atherosclerotic cardiovascular disease (ASCVD), with elevated low-density lipoprotein cholesterol (LDL-C) levels being a primary contributor. Despite standard statin therapy, individuals with ACS remain at high risk for recurrent cardiovascular events, particularly in the initial post-ACS period. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), such as evolocumab and alirocumab, offer a potential strategy to reduce LDL-C levels further and mitigate this residual risk. This review delves into the molecular mechanisms, effects on cholesterol metabolism, inflammatory modulation, and clinical outcomes associated with early administration of PCSK9 inhibitors following ACS.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low‐density lipoprotein cholesterol (LDL‐C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL‐C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice. [ABSTRACT FROM AUTHOR]

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates CD4+ T cell differentiation and inflammatory response, the latter ones mediate ulcerative colitis (UC) initiation. This study intended to explore the correlation of serum PCSK9 with disease activity, T helper (h)1/Th2/Th17 cells, and clinical response of tumor necrosis factor inhibitor (TNFi) in UC patients. Methods: In 65 UC patients underwent TNFi treatment, serum PCSK9 was evaluated at baseline (W0), week (W)2, W6, and W12 by enzyme-linked immunosorbent assays; meanwhile, Th1/Th2/Th17 cells were determined at W0 by flow cytometry. Besides, serum PCSK9 was detected in 65 healthy controls (HCs). Results: Serum PCSK9 was increased in UC patients compared to HCs (P<0.001), which also positively correlated with C-reactive protein (P=0.009), total Mayo score (P=0.018), Mayo-defined disease activity (P=0.020), Th1 (P=0.033), and Th17 (P=0.003) cells, but not Th2 cells (P=0.086) in UC patients. Interestingly, serum PCSK9 was steadily declined from W0 to W12 (P<0.001). W2-W0, W6-W0, and W12-W0 serum PCSK9 change (PCSK9 at W2, W6, or W12 minus PCSK9 at W0, respectively) was gradually becoming greater during TNFi treatment (P<0.001). Furthermore, forty-five (69.2%) patients achieved clinical response at W12, whose serum PCSK9 at W6 (P=0.041) and W12 (P=0.001) was lower, and W6-W0 (P=0.043), W12-W0 (P=0.019) serum PCSK9 change was more obvious compared to patients without clinical response at W12. Conclusions: Serum PCSK9 is positively related to disease activity, Th1, and Th17 cells in UC patients; further, its decline correlates with TNFi response achievement in these patients. [ABSTRACT FROM AUTHOR]

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low‐density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%–40% of FH cases. [ABSTRACT FROM AUTHOR]

• PCSK9 inhibition dramatically reduces both LDL-C and sdLDL-C to a similar degree. • Plasma 7-ketocholesterol levels were not significantly modulated by PCSK9 inhibition. • Changes in 7-ketocholesterol and VLDL-C after PCKS9 inhibition significantly correlated. • 7-Ketocholesterol may be carried by VLDL and lost during LDL formation. Oxidized forms of cholesterol (oxysterols) are implicated in atherogenesis and can accumulate in the body via direct absorption from food or through oxidative reactions of endogenous cholesterol, inducing the formation of LDL particles loaded with oxidized cholesterol. It remains unknown whether drastic reductions in LDL-cholesterol (LDL-C) are associated with changes in circulating oxysterols and whether small dense LDL (sdLDL) are more likely to carry these oxysterols and susceptible to the effects of PCSK9 inhibition (PCSK9i). We investigate the effect of LDL-C reduction accomplished via PCSK9i on changes in plasma levels of sdLDL-cholesterol (sdLDL-C) and a common, stable oxysterol, 7-ketocholesterol (7-KC), among 134 patients referred to our Preventive Cardiology clinic. Plasma lipid panel, sdLDL-C, and 7-KC measurements were obtained from patients before and after initiation of PCSK9i. The intervention caused a significant lowering of LDL-C (-55.4 %). The changes in sdLDL-C levels (mean reduction 51.4 %) were highly correlated with the reductions in LDL-C levels (R = 0.829, p < 0.001). Interestingly, whereas changes in plasma free 7-KC levels with PCSK9i treatment were much smaller than (-6.6 %) and did not parallel those of LDL-C and sdLDL-C levels, they did significantly correlate with changes in triglycerides and very low-density lipoprotein-cholesterol (VLDL-C) levels (R = 0.219, p = 0.025). Our findings suggest a non-preferential clearance of LDL subparticles as a consequence of LDL receptor upregulation caused by PCSK9 inhibition. Moreover, the lack of significant reduction in 7-KC with PCSK9i suggests that 7-KC may be in part carried by VLDL and lost during lipoprotein processing leading to LDL formation. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To evaluate the efficacy and safety of evolocumab， a proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitor， in lowering LDL-C levels in patients with coronary heart disease complicated with mild renal insufficiency. Methods Clinical data of patients diagnosed with coronary heart disease complicated with mild renal insufficiency in Department of Cardiology （estimated glomerular filtration rate （eGFR） 60-90 mL/（min·1.73 m2）） were retrospectively collected. All patients were divided into two groups according to the LDL-C lowering strategy. In the experimental group （n=50）， patients were treated with evolocumab， a PCSK9 inhibitor， combined with statins （rosuvastatin calcium tablets）， and their counterparts in the control group （n=42） were treated with statins （rosuvastatin calcium tablets） alone. LDL-C level， renal function indicators， side effects and adverse cardiovascular events at 1 and 3 months were observed between two groups. Results Compared with the control group， the LDL-C level at 1 month was significantly lower in the experimental group （（1.27±0.90） mmol/L vs. （1.75±0.82） mmol/L， P < 0.05）， and the LDL-C level 3 months was even lower （（0.94±0.44） mmol/L vs. （1.53±0.53） mmol/L， P < 0.05）. However， no significant differences were noted in the changes of renal function indicators at l and 3 months between two groups （all P > 0.05）. During 3-month treatment period， no adverse reactions， such as new-onset diabetes mellitus and neurocognitive dysfunction， were observed in both groups. The incidence of cardiovascular events （readmission for unstable angina， acute myocardial infarction and repeated percutaneous coronary intervention） and other adverse reactions （rash and myalgia） did not significantly differ between two groups （all P > 0.05）. Conclusions In coronary heart disease patients complicated with mild renal insufficiency， evolocumab combined with rosuvastatin can significantly reduce LDL-C levels at 1 and 3 months and maintain high safety compared with compared to rosuvastatin alone.

Scientific relevance. Cardiovascular diseases (CVD) are the leading cause of death worldwide. Dyslipidemia, as the pathophysiological basis of atherosclerosis, is the most important cause of CVD. Among the factors that modify this pathology, the World Health Organisation lists statins, which effectively reduce the cholesterol level. However, statin treatment compliance is not sufficient to achieve population-based lipid targets. This is a powerful stimulus for the creation of fundamentally new groups of lipid-lowering agents, in particular, antagonists of proprotein convertase subtilisin/kexin type 9 (PCSK9).Aim. The study aimed to review innovative approaches to developing a new generation of lipid-lowering agents, PCSK9 antagonists, and to evaluate the effectiveness, safety, and clinical potential of these medicines.Discussion. PCSK9 antagonists significantly increase the effectiveness of lipid-lowering therapy when combined with statins and are an effective monotherapy in patients with contraindications for statins. PCSK9 monoclonal antibodies, as well as inclisiran, have a favourable risk–benefit ratio. However, the high cost of commercially available PCSK9 antagonists limits their clinical use. A number of promising directions exist for developing new PCSK9 antagonists that have fundamentally different mechanisms of action, such as adnectins; genome editing with CRISPR/Cas9; combining small molecules with low molecular weight PCSK9 inhibitors; PCSK9 vaccines; and antisense oligonucleotides. Medicinal products from these groups are currently at various stages of preclinical and clinical development.Conclusions. Therefore, new lipid-lowering agents can be developed by synthesising high and low molecular weight PCSK9 ligands and by altering the genetic mechanisms of PCSK9 synthesis. The innovative medicines considered in this review are highly effective, and most have shown no signs of toxicity at the pre-authorisation stage.

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality, being twofold to fourfold more common in patients with type 2 diabetes mellitus (T2DM) than in individuals without diabetes. However, despite this decade-old knowledge, the identification of a specific prognostic risk biomarker remains particularly challenging. Methods Taking advantage of a large sample of Caucasian patients (n = 529) with a diagnosis of T2DM followed for a median of 16.8 years, the present study was aimed at testing the hypothesis that fasting serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could be prognostic for major adverse cardiovascular events (MACE) and all-cause mortality. Results Median levels of PCSK9 were 259.8 ng/mL, being higher in women compared to men and increasing even more in the presence of a complication (e.g., diabetic kidney disease). PCSK9 positively correlated with markers of blood glucose homeostasis (e.g., HbA1c, fasting insulin and HOMA-IR) and the atherogenic lipid profile (e.g., non-HDL-C, apoB and remnant cholesterol). Serum PCSK9 predicted new-onset of MACE, either fatal or non-fatal, only in women (Odds Ratio: 2.26, 95% CI 1.12–4.58) and all-cause mortality only in men (Hazard Ratio: 1.79, 95% CI 1.13–2.82). Conclusions Considering that up to two-thirds of individuals with T2DM develop ASCVD in their lifetime, the assessment of circulating PCSK9 levels can be envisioned within the context of a biomarker-based strategy of risk stratification. However, the sex difference found highlights an urgent need to develop sex-specific risk assessment strategies. Trial registration: It is a retrospective study.

Lowering low‐density lipoprotein cholesterol (LDL‐C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL‐C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline‐recommended LDL‐C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease‐related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL‐C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice‐yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL‐C levels by ≈50% versus placebo when added to maximally tolerated statins. Long‐term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021,

The purpose of this study was to investigate the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and renal function impairment in type 2 diabetes mellitus (T2DM) patients. PCSK9 levels were measured in T2DM patients, streptozotocin plus high-fat diet (STZ + HFD) mice, human proximal tubular epithelial (HK-2) cells treated with high glucose plus palmitic acid (HGPA) and the corresponding control groups. The T2DM patients were further divided into three groups according to serum PCSK9 levels. An analysis of clinical data was conducted, and a binary logistic regression model was used to test the relationship between potential predictors and urine albumin/urine creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). PCSK9 levels were higher in the DM group than in the control group in humans, mice and HK-2 cells. The systolic blood pressure (SBP), serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), and urine α1-MG/urine creatinine ratio (UαCR) values in PCSK9 tertile 3 were significantly higher than those in PCSK9 tertile 1 (p < 0.05). The DBP and UACR values were significantly higher in PCSK9 tertile 3 than in PCSK9 tertile 1 and PCSK9 tertile 2 (both p < 0.05). In addition, URCR values were significantly higher in PCSK9 tertile 3 and PCSK9 tertile 2 than in PCSK9 tertile 1 (both p < 0.05). Serum PCSK9 levels were positively correlated with SBP, Scr, BUN, TG, URCR, UαCR and UACR but inversely correlated with eGFR. In STZ + HFD mice, serum PCSK9 levels were positively correlated with Scr, BUN and UACR, which was consistent with the findings in the patients. A logistic regression model revealed that serum PCSK9 is an independent risk factor for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m2. The ROC curve showed that 170.53 ng/mL and 337.26 ng/mL PCSK9 were the best cutoff values for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m2, respectively. Serum PCSK9 levels are associated with renal function impairment in T2DM patients and in some patients lower PCSK9 may be helpful to decrease chronic kidney disease. [ABSTRACT FROM AUTHOR]

Hypoxia and its induced autophagy are involved in the initiation and progression of liver fibrosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a potential regulator of autophagy. Our previously reported study found that PCSK9 expression increased in liver fibrosis and that anti-PCSK9 treatment alleviated liver injury. This study aimed to investigate the mechanism of anti-PCSK9 treatment on liver fibrosis by inhibiting hypoxia-induced autophagy. Carbon tetrachloride-induced mouse liver fibrosis and mouse hepatocyte line AML12, cultured under the hypoxic condition, were established to undergo PCSK9 inhibition. The degree of liver fibrosis was shown with histological staining. The reactive oxygen species (ROS) generation was detected by flow cytometry. The expression of PCSK9, hypoxia-inducible factor-1α (HIF-1α), and autophagy-related proteins was examined using Western blot. The autophagic flux was assessed under immunofluorescence and transmission electron microscope. The mouse liver samples were investigated via RNA-sequencing to explore the underlying signaling pathway. The results showed that PCSK9 expression was upregulated with the development of liver fibrosis, which was accompanied by enhanced autophagy. In vitro data verified that PCSK9 increased via hypoxia and inflammation, accompanied by the hypoxia-induced autophagy increased. Then, the validation was acquired of the bidirectional interaction of hypoxia-ROS and PCSK9. The hypoxia reversal attenuated PCSK9 expression and autophagy. Additionally, anti-PCSK9 treatment alleviated liver inflammation and fibrosis, reducing hypoxia and autophagy in vivo. In mechanism, the AMPK/mTOR/ULK1 signaling pathway was identified as a target for anti-PCSK9 therapy. In conclusion, anti-PCSK9 treatment could alleviate liver inflammation and fibrosis by regulating AMPK/mTOR/ULK1 signaling pathway to reduce hypoxia-induced autophagy in hepatocytes. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves an important role in maintaining plasma cholesterol levels, and fatty acid metabolism is involved in the progression of various types of cancer. In the present study, the role of PCSK9 in the development of esophageal squamous cell carcinoma (ESCC) was investigated. PCSK9 expression was compared between ESCC and normal esophageal epithelial tissues using reverse transcription-quantitative PCR. In addition, the association between PCSK9 expression and clinical staging and prognosis was assessed by immunohistochemistry. The effects of PCSK9 overexpression or knockdown on cell proliferation was evaluated using Cell Counting Kit-8 and colony formation assays. The invasion and migration of cancer cells was assessed using wound healing and Transwell assays. Western blotting was performed to evaluate changes in the expression levels of epithelial-mesenchymal transition (EMT)-related proteins. ELISA was performed to detect the effects of PCSK9 on chemokine (C-C motif) ligand 25 (CCL25) secretion. The results revealed that PCSK9 was highly expressed in ESCC tissues compared with that in normal esophageal tissues, and the high expression of PCSK9 was associated with a poor prognosis. Furthermore, PCSK9 could promote the proliferation, migration and invasion of ESCC cells in vitro. Mechanistically, PCSK9 could promote EMT by secreting CCL25. In conclusion, patients with ESCC may benefit from a novel therapeutic strategy based on these findings. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in lowering LDL-C levels in patients with coronary heart disease complicated with mild renal insufficiency. Methods Clinical data of patients diagnosed with coronary heart disease complicated with mild renal insufficiency in Department of Cardiology (estimated glomerular filtration rate (eGFR) 60-90 mL/(min · 1.73 m²)) were retrospectively collected. All patients were divided into two groups according to the LDL-C lowering strategy. In the experimental group (n=50, patients were treated with evolocumab, a PCSK9 inhibitor, combined with statins (rosuvastatin calcium tablets), and their counterparts in the control group (n=42) were treated with statins (rosuvastatin calcium tablets) alone. LDL-C level, renal function indicators, side effects and adverse cardiovascular events at 1 and 3 months were observed between two groups. Results Compared with the control group, the LDL-C level at 1 month was significantly lower in the experimental group ((1.27±0.90) mmol/L vs. (1.75±0.82) mmol/L, P < 0.05, and the LDL-C level 3 months was even lower ((0.94±0.44) mmol/L vs. (1.53±0.53) mmol/L, P < 0.05. However, no significant differences were noted in the changes of renal function indicators at l and 3 months between two groups (all P > 0.05. During 3-month treatment period, no adverse reactions, such as new-onset diabetes mellitus and neurocognitive dysfunction, were observed in both groups. The incidence of cardiovascular events (readmission for unstable angina, acute myocardial infarction and repeated percutaneous coronary intervention) and other adverse reactions (rash and myalgia) did not significantly differ between two groups (all P > 0.05. Conclusions In coronary heart disease patients complicated with mild renal insufficiency, evolocumab combined with rosuvastatin can significantly reduce LDL-C levels at 1 and 3 months and maintain high safety compared with compared to rosuvastatin alone. [ABSTRACT FROM AUTHOR]

Background: To date, optimal agents for low-density lipoprotein cholesterol (LDL-C) reduction in patients with established atherosclerotic cardiovascular disease are still being explored. Thus, we evaluated the efficiency of novel LDL-C-lowering therapies in the secondary prevention of cardiovascular events. Methods: We included randomized clinical trials (RCTs) that explored the effects of different LDL-C lowering agents including alirocumab, evolocumab, and bempedoic acid in adult patients with cardiovascular disease. Several databases were searched from inception through 2022. The safety endpoint includes new-onset diabetes, serious adverse events, and neurocognitive disorders with at least 1 year of follow-up. The efficacy outcomes included composite adverse cardiovascular outcomes, all-cause death, and cardiovascular death. Results: Seven RCTs comprising 53,106 patients were included in this research. Bempedoic acid ranked first in reducing the risk of new-onset diabetes (risk ratio [RR] 0.72, 95% credible interval [CrI] 0.52–0.99) and risk of the composite cardiovascular outcome (RR 0.75, 95% CrI 0.57–0.99). Meta-regression analysis demonstrated that elevated risk of new-onset diabetes was positively correlated with a significant reduction in LDL-C levels (p = 0.03). All treatment agents were associated with a decreased risk of a composite adverse cardiovascular outcome. Conclusions: The present analysis showed that bempedoic acid ranked first in reducing the risk of a composite cardiovascular outcome. In addition, it ranked first in reducing the risk of new-onset diabetes compared with placebo and evolocumab. Our analysis also suggests that the increased risk of new-onset diabetes might be associated with a reduction in LDL-C levels. Besides, the present analysis found that alirocumab ranked first in decreasing all-cause mortality and cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Abstract PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE−/− mice.

AbstractPurpose The purpose of this study was to investigate the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and renal function impairment in type 2 diabetes mellitus (T2DM) patients.Methods PCSK9 levels were measured in T2DM patients, streptozotocin plus high-fat diet (STZ + HFD) mice, human proximal tubular epithelial (HK-2) cells treated with high glucose plus palmitic acid (HGPA) and the corresponding control groups. The T2DM patients were further divided into three groups according to serum PCSK9 levels. An analysis of clinical data was conducted, and a binary logistic regression model was used to test the relationship between potential predictors and urine albumin/urine creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR).Results PCSK9 levels were higher in the DM group than in the control group in humans, mice and HK-2 cells. The systolic blood pressure (SBP), serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), and urine α1-MG/urine creatinine ratio (UαCR) values in PCSK9 tertile 3 were significantly higher than those in PCSK9 tertile 1 (p

Our previous research revealed that an increase in PCSK9 is linked to aggravated inflammation in the kidneys of mice affected by a high‐fat diet and streptozotocin (HFD/STZ) or in HGPA‐induced HK‐2 cells. Furthermore, the cGAS/STING pathway has been reported to be involved in diabetic nephropathy (DN). Therefore, in this study, we aimed to examine the correlation between the proinflammatory effect of PCSK9 and the cGAS/STING pathway in DN. We used PCSK9 mAbs to inhibit PCSK9 in vivo and PCSK9 siRNA in vitro and measured the inflammatory phenotype in HFD/STZ‐treated mice or HGPA‐induced HK‐2 cells, and observed decreased blood urea nitrogen, creatinine, UACR, and kidney injury in response to the PCSK9 mAb in HFD/STZ‐treated mice. Moreover, IL‐1 β, MCP‐1, and TNF‐α levels were reduced by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. We observed increased mtDNA damage and activation of the cGAS‐STING signaling pathway during DN, as well as the downstream targets p‐TBK1, p‐NF‐κB p65, and IL‐1β. In a further experiment with an HGPA‐induced DN model in HK‐2 cells, we revealed that mtDNA damage was increased, which led to the activation of the cGAS/STING system and its downstream targets. Notably, the cGAS‐STING signaling pathway was inhibited by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. In addition, inhibition of STING with C‐176 in HGPA‐induced HK‐2 cells markedly blocked inflammation. In conclusion, we report for the first time that PCSK9 triggers mitochondrial DNA damage and activates the cGAS‐STING pathway in DN, which leads to a series of inflammation cascades. PCSK9‐targeted intervention can effectively reduce DN inflammation and delay its progression. Moreover, the inhibition of STING significantly abrogated the inflammation triggered by HGPA in HK‐2 cells. [ABSTRACT FROM AUTHOR]

Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality, being twofold to fourfold more common in patients with type 2 diabetes mellitus (T2DM) than in individuals without diabetes. However, despite this decade-old knowledge, the identification of a specific prognostic risk biomarker remains particularly challenging. Methods: Taking advantage of a large sample of Caucasian patients (n = 529) with a diagnosis of T2DM followed for a median of 16.8 years, the present study was aimed at testing the hypothesis that fasting serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could be prognostic for major adverse cardiovascular events (MACE) and all-cause mortality. Results: Median levels of PCSK9 were 259.8 ng/mL, being higher in women compared to men and increasing even more in the presence of a complication (e.g., diabetic kidney disease). PCSK9 positively correlated with markers of blood glucose homeostasis (e.g., HbA1c, fasting insulin and HOMA-IR) and the atherogenic lipid profile (e.g., non-HDL-C, apoB and remnant cholesterol). Serum PCSK9 predicted new-onset of MACE, either fatal or non-fatal, only in women (Odds Ratio: 2.26, 95% CI 1.12–4.58) and all-cause mortality only in men (Hazard Ratio: 1.79, 95% CI 1.13–2.82). Conclusions: Considering that up to two-thirds of individuals with T2DM develop ASCVD in their lifetime, the assessment of circulating PCSK9 levels can be envisioned within the context of a biomarker-based strategy of risk stratification. However, the sex difference found highlights an urgent need to develop sex-specific risk assessment strategies. Trial registration: It is a retrospective study. [ABSTRACT FROM AUTHOR]

Objective: Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in the autoimmune disease pathology by regulating T helper (Th) cell differentiation, NF-κB pathway, toll-like receptor 4, etc. This study intended to investigate the association of serum PCSK9 with disease activity, Th cells, and treatment response in ankylosing spondylitis (AS) patients. Methods: Eighty-nine active AS patients were enrolled in this multicenter, prospective study. Serum was collected from AS patients at week (W)0, W4, W8, and W12, as well as from 20 osteoarthritis patients and 20 healthy controls after enrollment to detect PCSK9 by ELISA. Based on the ASAS40 response at W12, AS patients were classified as responders and non-responders. Results: PCSK9 was increased in AS patients versus healthy controls (P < 0.001) and osteoarthritis patients (P = 0.006). In AS patients, PCSK9 was positively linked with C-reactive protein (CRP) (P = 0.003) and ASDAS-CRP (P = 0.017), but not with other clinical properties (P > 0.05). Besides, PCSK9 was negatively correlated with interleukin-4 (P = 0.034), positively associated with Th17 cells (P = 0.005) and interleukin-17A (P = 0.014), but did not relate to Th1 cells, interferon-γ, or Th2 cells (all P > 0.05). Additionally, PCSK9 was decreased from W0 to W12 in general AS patients (P < 0.001) and responders (P < 0.001) but remained unchanged in non-responders (P = 0.129). Moreover, PCSK9 was lower at W4 (P = 0.045), W8 (P = 0.008), and W12 (P = 0.004) in responders versus non-responders. Furthermore, the treatment options did not affect the PCSK9 level (P > 0.05). Conclusion: Serum PCSK9 is positively associated with disease activity and Th17 cells, while its short-term decline reflects desirable treatment response in AS patients. [ABSTRACT FROM AUTHOR]

Abstract Elevated low-density lipoprotein cholesterol (LDL-C) level is associated with an increased risk of atherosclerotic cardiovascular disease. Although high-intensity lipid-lowering therapies with statins and ezetimibe are highly effective for reducing LDL-C levels, over half of high-risk patients do not achieve guideline-recommended LDL-C goals. Thus, there is a significant gap between treatment guidelines and their implementation in daily clinical practice. The major causes are individual variability in the response to lipid-lowering therapies and variation in treatment adherence. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies combined with statins provide marked and consistent reduction in LDL-C levels; however, poor adherence due to the need for subcutaneous injections every 2 or 4 weeks and high cost are major obstacles to their use in real-world clinical settings. Inclisiran, a recently approved novel small interfering ribonucleic acid (siRNA) molecule that inhibits PCSK9 synthesis, provides robust and long-term reduction in LDL-C levels with a low inter-individual variability in the LDL-C-lowering response. Moreover, its administration by biannual injection is expected to greatly improve treatment adherence. Clinical trials of this drug lasting for up to 4 years showed acceptable safety profiles, and ongoing studies accumulate evidence of its longer-term safety. This narrative review summarizes the available evidence on the efficacy and safety of inclisiran and analyzes its potential to overcome the gap between guideline recommendations and real-world clinical practice in current LDL-C-lowering therapies, with a focus on reduced LDL-C level variability and improved treatment adherence.

Xiaoxiao Zhao,1,&ast; Li Song,1,&ast; Jiannan Li,1 Jinying Zhou,1 Nan Li,1 Shaodi Yan,2 Runzhen Chen,1 Ying Wang,1 Chen Liu,1 Peng Zhou,1 Zhaoxue Sheng,1 Yi Chen,1 Hanjun Zhao,1 Hongbing Yan2 1Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongbing Yan, Fuwai Hospital, Chinese Academy of Medical Sciences, 12 Langshan Road, Shenzhen, 518000, People’s Republic of China, Tel +86-13701339287, Email hbyanfuwai2018@163.com Hanjun Zhao, Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, No. 167, Beijing, 100037, People’s Republic of China, Tel +86-15210020808, Email 15210020808@163.comBackground and Aims: This study aimed to determine whether convertase subtilisin/kexin type 9 (PCSK9)-associated cardiovascular risk is modulated by triglyceride-glucose (TyG) in ST-segment elevation myocardial infarction (STEMI) patients with primary percutaneous coronary disease (PCI).Methods: A total of 1541 patients with STEMI (aged ≥ 18 years) undergoing primary PCI were consecutively enrolled between March 2017 and March 2019.Outcomes: When stratifying the overall population according to TyG indices less than or greater than the median (TyG median = 9.07) as well as according to quartiles of PCSK9 levels, higher TyG index levels were significantly associated with all-cause mortality only when TyG levels were 9.07 or higher (ie, relative to quartile 1 [Q1], the adjusted HR for all-cause mortality was 3.20 [95% CI, 0.54– 18.80] for Q2, p = 0.199; 7.89 [95% CI, 1.56– 40.89] for Q3, p = 0.013; and 5.61 [95% CI, 1.04– 30.30] for Q4, p = 0.045. During a median follow-up period of 1.96 years, the HR for all-cause mortality was higher in the subset of patients with TyG ≥median and PCSK9 ≥median (p for trend = 0.023) among those with type 2 diabetes mellitus (T2DM). However, there were no statistically significant differences among the subgroups. Among T2DM patients with a TyG index greater than the median, the Kaplan-Meier curve showed that patients with the highest PCSK9 levels had an increased risk of all-cause mortality (log-rank p = 0.017) and cardiac-cause mortality (log-rank p = 0.037) compared with lower PCSK9 quartile levels.Conclusion: Elevated PCSK9 levels are related to all-cause mortality and cardiac-related mortality when TyG levels are greater than the median, but not when levels are less than the median. This suggests a potential benefit of lowering circulating PCSK9 levels in STEMI patients with insulin resistance.Keywords: triglyceride glucose index, proprotein convertase subtilisin/kexin type 9, mortality, type 2 diabetes, ST-segment elevation myocardial infarction, primary percutaneous coronary intervention

PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE−/− mice. [ABSTRACT FROM AUTHOR]

Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low‐density lipoprotein cholesterol and incident cardiovascular disease, including stroke. However, the clinical relevance of circulating PCSK9 levels has been poorly elucidated in the general population, particularly in association with subclinical cerebrovascular disease including cerebral small vessel disease (CSVD) and intracranial artery stenosis (ICAS). Methods: In community‐dwelling Japanese men (n = 526) aged 46–82 years without a history of cardiovascular disease, the associations of serum PCSK9 levels with the prevalence of CSVD and ICAS were assessed using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity and cerebral microbleeds. Results: The median (interquartile range) age at baseline and serum PCSK9 levels were 69 (63–74) years and 240 (205–291) ng/ml, respectively. After adjusting for traditional cardiovascular risk factors including low‐density lipoprotein cholesterol, multivariable Poisson regression with robust error variance revealed a significant association between PCSK9 levels (per 1 SD) and ICAS (relative risks 1.18, 95% confidence interval 1.02–1.37). Multivariable ordinal logistic regression for ICAS, with stenosis graded as mild (<50%) or moderate–severe (≥50%), revealed a similar association (common odds ratio 1.31, 95% confidence interval 1.04–1.64). However, no significant association was observed between serum PCSK9 levels and CSVD. Conclusions: Higher circulating PCSK9 levels were independently associated with an ICAS prevalence but not with CSVD prevalence. The quantification of circulating PCSK9 levels may help to identify individuals at high risk for cerebrovascular disease in the general population. [ABSTRACT FROM AUTHOR]

Objective: Our previous study reveals that proprotein convertase subtilisin/kexin type 9 (PCSK9) is positively related to inflammatory markers, T helper (Th)‐17 cells, and treatment response in ankylosing spondylitis (AS) patients. Subsequently, this study aimed to explore the effect of PCSK9 on Th cell differentiation and its potential molecular mechanism in AS. Methods: Serum PCSK9 was determined by enzyme‐linked immunosorbent assay in 20 AS patients and 20 healthy controls (HCs). Then naïve CD4+ T cells were isolated from AS patients and infected with PCSK9 overexpression or knockdown adenovirus followed by polarization assay. Afterward, PMA (an NF‐κB activator) was administrated. Results: PCSK9 was increased in AS patients compared to HCs (p <.001), and it was positively related to Th1 cells (p =.050) and Th17 cells (p =.039) in AS patients. PCSK9 overexpression increased the CD4+IFN‐γ+ cells (p <.05), CD4+IL‐17A+ cells (p <.01), IFN‐γ (p <.01), and IL‐17A (p <.01), while it exhibited no effect on CD4+IL‐4+cells or IL‐4 (both p >.05); its knockdown displayed the opposite function on them. Moreover, PCSK9 overexpression upregulated the p‐NF‐κB p65/NF‐κB p65 (p <.01), while it had no effect on p‐ERK/ERK or p‐JNK/JNK (both p >.05); its knockdown decreased p‐NF‐κB p65/NF‐κB p65 (p <.01) and p‐JNK/JNK (p <.05). Then, PMA upregulates p‐NF‐κB p65/NF‐κB p65 (p <.001) and increased CD4+IFN‐γ+ cells, CD4+IL‐17A+ cells, IFN‐γ, and IL‐17A (all p <.01), also it alleviated the effect of PCSK9 knockdown on NF‐κB inhibition and Th cell differentiation (all p <.01). Conclusion: PCSK9 enhances Th1 and Th17 cell differentiation in an NF‐κB‐dependent manner in AS, while further validation is necessary. [ABSTRACT FROM AUTHOR]