Role Of Proprotein Convertase Subtilisin/kexin Type 9 Research Articles

Association of PCSK-9 with the Biomarkers of Type-2 Diabetes and its Complications in the Indian Population: a Pilot Study.

Proprotein convertase subtilisin/kexin type-9 (PCSK-9) is a serine protease with profound effects on plasma LDL-C, the major risk factor for cardiovascular diseases (CVDs). However, plasma PCSK-9 level and its association with the biomarkers of CVDs, diabetes, and associated complications have not yet been reported in the northeastern population of India. Of the total cohort (n = 233), we analyzed healthy controls (HC; n = 50), freshly diagnosed type-2-diabetes mellitus (T2DM-FD; n = 46), T2DM treated (T2DM-T; n = 49), diabetic nephropathy (T2DM-N; n = 43), and diabetic dyslipidemia (T2DM-DL; n = 45) subjects. Plasma PCSK-9 and other biological determinants associated with T2DM, CVD, and nephrotic dysfunction were assessed. The level of plasma PCSK-9 in HC, T2DM-FD, T2DM-T, T2DM-N, and T2DM-DL groups was found to be 184.1 ± 13.83, 183.1 ± 24.4.3, 241.8 ± 75.42, 403.7 ± 85.94, and 641.3 ± 135.5 ng/mL, respectively, indicating its role in the severity of the here-mentioned complications. Moreover, plasma PCSK-9 levels further showed a significant correlation with the biomarkers of hyperglycemia, particularly HbA1c, as well as LDL-C in T2DM-FD, T2DM-N, and T2DM-DL subjects of the Indian population, while moderate association in T2DM-T subjects. Our first-of-its-kind clinical study aiming to quantify the circulatory PCSK-9 level in the Indian population concluded that elevated PCSK-9 was significantly associated with the severity of diabetes and associated complications. Moreover, such elevation in PCSK-9 might be attributed to the lipid- and glucoselowering medication-induced SREBP-2-dependent mechanisms. Since our conclusion is based on a pilot study, further cohort studies in larger populations of India are required to get a generalization regarding the role of PCSK-9 in DM and associated complications.

PCSK9 promotes tumor cell proliferation and migration by facilitating CCL25 secretion in esophageal squamous cell carcinoma.

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.

Roles of PCSK9 in the pathogenesis of periodontal disease.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors are FDA-approved drugs recommended for high-risk patients with LDL-cholesterol (LDL-c) levels ≥ 70 mg/dl. Several studies have also investigated the relationship between PCSK9 and periodontitis. Specifically, studies have investigated the association between periodontitis and periodontal PCSK9 levels in humans, and periodontium status in PCSK9-knockout versus wild-type mice. While a positive association between periodontitis and periodontal PCSK9 levels has been noted, the findings on the comparison of periodontium status between PCSK9-knockout and wild-type mice have been inconsistent. Different methodologies among these studies may explain this discrepancy. Future experimental studies on the impact of pharmacological PCSK9 inhibition on periodontal status as well as observational studies comparing periodontium status between patients receiving PCSK9 inhibitors and those receiving other lipid-lowering drugs will shed light on the role of PCSK9 in periodontal health and disease.

PCSK9 inhibition interrupts the cross-talk between keratinocytes and macrophages and prevents UVB-induced skin damage

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that promotes the degradation of low-density lipoprotein receptors. It is involved in hyperlipidemia as well as other diseases, such as cancer and skin inflammation. However, the detailed mechanism for PCSK9 on ultraviolet B (UVB)-induced skin lesions was not clear. Thus, the role and possible action mechanism of PCSK9 in UVB-induced skin damage in mice were studied here using siRNA and a small molecule inhibitor (SBC110736) against PCSK9. Immunohistochemical staining revealed a significant increase in PCSK9 expression after UVB exposure, indicating the possible role of PCSK9 in UVB damage. Skin damage, increase in epidermal thickness, and keratinocyte hyperproliferation were significantly alleviated after treatment with SBC110736 or siRNA duplexes, compared with that in the UVB model group. Notably, UVB exposure triggered DNA damage in keratinocytes, whereas substantial interferon regulatory factor 3 (IRF3) activation was observed in macrophages. Pharmacologic inhibition of STING or cGAS knockout significantly reduced UVB-induced damage. In the co-culture system, supernatant from UVB-treated keratinocyte induced IRF3 activation in macrophages. This activation was inhibited with SBC110736 and by PCSK9 knockdown. Collectively, our findings reveal that PCSK9 plays a critical role in the crosstalk between damaged keratinocytes and STING activation in macrophages. The interruption of this crosstalk by PCSK9 inhibition may be a potential therapeutic strategy for UVB-induced skin damage.

Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release.

Atherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases.

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Beyond Lipids: The Role in Oxidative Stress and Thrombosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.

Proprotein Convertase Subtilisin/Kexin Type 9 and Inflammation: An Updated Review.

The function of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a novel plasma protein, has mainly been involved in cholesterol metabolism in the liver, while, more interestingly, recent data have shown that PCSK9 also took part in the modulation of inflammation, which appeared to be another explanation for the reduction of cardiovascular risk by PCSK9 inhibition besides its significant effect on lowering lower-density lipoprotein cholesterol (LDL-C) concentration. Overall, a series of previous studies suggested an association of PCSK9 with inflammation. Firstly, PCSK9 is able to induce the secretion of proinflammatory cytokines in macrophages and in other various tissues and elevated serum PCSK9 levels could be observed in pro-inflammatory conditions, such as sepsis, acute coronary syndrome (ACS). Secondly, detailed signaling pathway studies indicated that PCSK9 positively regulated toll-like receptor 4 expression and inflammatory cytokines expression followed by nuclear factor-kappa B (NF-kB) activation, together with apoptosis and autophagy progression. Besides, PCSK9 enhanced and interacted with scavenger receptors (SRs) of inflammatory mediators like lectin-like oxidized-LDL receptor-1 (LOX-1) to promote inflammatory response. Additionally, several studies also suggested that the role of PCSK9 in atherogenesis was intertwined with inflammation and the interacting effect shown between PCSK9 and LOX-1 was involved in the inflammatory response of atherosclerosis. Finally, emerging clinical trials indicated that PCSK9 inhibitors could reduce more events in patients with ACS accompanied by increased inflammatory status, which might be involved in its attenuating impact on arterial plaque. Hence, further understanding of the relationship between PCSK9 and inflammation would be necessary to help prevent and manage the atherosclerotic cardiovascular disease (ASCVD) clinically. This review article will update the recent advances in the link of PCSK9 with inflammation.

PCSK9 and Inflammation: Their Role in Autoimmune Diseases, with a Focus on Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Despite a clear epidemiological link between autoimmune disease and cardiovascular (CV) risk exists, pathophysiological explanations are extremely complex and far from being elucidated. Dysregulation of metabolic pathways and chronic low-grade inflammation represent common pathways, but CV risk still remains underestimated in patients with autoimmune diseases. Among different candidate mediators, pro-protein convertase subtilisin/kexin type 9 (PCSK9) is attracting growing attention, due to a combined effect on lipid metabolism and inflammatory response. Studies on PCSK9 inhibitors have established a clear benefit on CV outcome without an established effect on inflammation. Conversely, evidence from sepsis and HIV infection strongly supports a pro-inflammatory role of PCSK9. Still, the role of PCSK9 in autoimmune diseases is uncertain. So far, reported clinical findings are controversial and likely reflect the poor knowledge of PCSK9 activity on monocyte/macrophage migration and activation. The complex signaling network around PCSK9 synthesis and metabolism may also have a role, especially concerning the involvement of scavenger receptors, such as CD36. Such complexity in PCSK9 signaling seems particularly evident in autoimmune disease model. This would also potentially explain the observed independency between lipid profile and PCSK9 levels, the so-called "lipid paradox". In this narrative review, we will summarize the current knowledge about the complex network of PCSK9 signaling. We will focus on upstream and downstream pathways with potential implication in autoimmune disease and potential effects of PCSK9 inhibiting strategies.

Prognostic value of PCSK9 Levels in Non-ST elevation myocardial infarction patients undergoing percutaneous coronary intervention

Abstract Background The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in predicting major adverse cardiovascular events (MACEs) in Non-ST elevation myocardial infarction (NSTEMI) patients is still an open question and the PCSK9 concentration of clinical usefulness remains unknown in guiding treatment. Purpose To explore the role of PCSK9 in predicting major adverse cardiovascular events (MACEs) in Non-ST elevation myocardial infarction patients. Methods 272 patients with NSTEMI were included in our study, all patients received PCI therapy after admission. Patients were followed up for 1 year and MACEs were recored. Their baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high, medium and low PCSK9 groups and the associations of PCSK9 with other biomarkers and MACEs were evaluated. Results The results showed that PCSK9 levels was related to levels of lipoproteins, high-sensitivity C-reactive protein (r=0.162, P=0.008), platelet volume distribution width (r=0.299, P<0.001) and D-dimer (r=0.285, P<0.001). And the concentrations of PCSK9 was greater higher in people with MACEs (137.2ng/ml vs 243.6ng/ml) (Fig. 1A). The Kaplan-Meier curves showed patients with high PCSK9 level had lower event-free survival rate (Fig. 1B). Survival analysis indicated high level of PCSK9 predicted MACEs independently after adjusted for traditional cardiovascular risk factors and GRACE score (HR=2.646, 95CI%: 1.047–6.686, P=0.027) (Fig. 1C, Fig. 2). Subgroup analysis demonstrated the prognostic value of high PCSK9 level was greater for patients classified by the GRACE score as high risk (Fig. 1D). Conclusions In a NSTEMI setting, the concentration of PCSK9 is associated with hypercoagulability and hyper-inflammation. High levels of PCSK9 independently predict future MACEs in NSTEMI patients, particularly those classified by the GRACE score as high risk. Funding Acknowledgement Type of funding sources: None.

Strong association between serum PCSK9 and cardiovascular disease in patients with moderate chronic kidney diseases - The GCKD study

Background and Aims: Chronic Kidney Disease (CKD) is a major health burden worldwide. Impaired kidney function gives rise to dyslipidemia, a common risk factor for cardiovascular diseases (CVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Currently, no studies are available about the role of PCSK9 in CVD in a large cohort of CKD patients.

Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis

The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%–20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

Autocrine effects of PCSK9 on cardiomyocytes

Proprotein convertase subtilisin kexin type 9 (PCSK9) is in the focus of cardiovascular research due to its role in hepatic low density lipoprotein (LDL) clearance. However, extrahepatic expression of PCSK9 such as in cardiomyocytes and its regulation by oxidized LDL (oxLDL) put notion on extrahepatic effects of PCSK9 as well. This study was aimed to reveal the role of PCSK9 in oxLDL-dependent regulation of cardiomyocyte function. Adult rat and mouse ventricular cardiomyocytes and isolated perfused hearts were used. OxLDL was applied to increase PCSK9 expression in cardiomyocytes. Cell function was analyzed by load-free cell shortening as well as left ventricular developed pressure of isolated hearts. OxLDL decreased shortening in wild-type-derived mouse cardiomyocytes but not in those isolated from PCSK9 knockout mice. Overexpression of human PCSK9 in rat cardiomyocytes reduced shortening in the absence of oxLDL. Addition of recombinant PCSK9 mimicked these effects. In cardiomyocytes, oxLDL induced PCSK9 release into the supernatant. Inhibition of PCSK9 by Pep 2–8 or alirocumab attenuated the oxLDL-induced loss of cardiomyocyte shortening. Cardiomyocytes express surfeit locus protein 4 (SURF-4), a protein required for PCSK9 secretion in human embryonic kidney cells (HEK 293 T), and silencing of SURF-4 reduced the oxLDL effects on cardiomyocytes. In isolated perfused rat hearts PCSK9 inhibition by alirocumab improved the function. In addition, left ventricular function of isolated hearts from PCSK9 knockout mice was increased under basal conditions as well as at 10 min and 120 min of reperfusion following 45 min of ischemia. Collectively, the data show that cardiomyocytes express and release PCSK9 that acts in an autocrine way on cardiomyocytes and impairs their function.

Procalcific effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) in chronic kidney disease (CKD)

Abstract Aim PCSK9 has been recently associated with a higher rate of calcification in hypercholesterolemic, diabetes and CKD patients. The aim of this study was thus to investigate the role of PCSK9 in VC process, under uremic condition, both on in vivo and in vitro experimental settings. Methods Sprauge Dawley rats were fed a standard diet (SD, n=11) or uremic diet (UD, n=11) for 6 weeks. Calcium crystals in aortas were visualized by von Kossa staining and quantified by a colorimetric assay and plasma total cholesterol determined. Control and PCSK9-overexpressing smooth muscle cells (SMCsPCSK9) were cultured with 2.5% FCS ± Pi for 7 days. Hydroxyapatite deposition by SMCs was measured by a colorimetric assay. The number and the content of pro-calcific extracellular vesicles (EVs) budding from the cells were determined. Results The hyperphosphatemia secondary to CKD lead to rat aortic calcification (+7.3-fold) and a significant increase in TC and PCSK9 levels (+1.4 and +2.7-fold, respectively). Higher expression of PCSK9 was also observed in kidney (+4.8-fold) and liver (+1.5-fold). SMCsPCSK9 showed higher extracellular calcium deposition (+1.4-fold) in response to Pi and increase EVs production (+7-fold). The incubation of control cells with recombinant PCSK9 did not induce extracellular calcium deposition. Conclusions Our study suggest a positive effect of intracellular PCSK9 on vascular calcification in CKD condition. Pro-calcific budding of EVs seems one of the possible mediators of this process. PCSK9 and calcification Funding Acknowledgement Type of funding source: None

PCSK9: A Potential Therapeutic Target for Sepsis.

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is often upregulated in the presence of sepsis and infectious diseases. In sepsis, PCSK9 degraded the low-density lipoprotein cholesterol (LDL) receptors (LDL-R) of the hepatocytes and the very low-density lipoprotein cholesterol receptors (VLDL-R) of the adipocytes, which then subsequently reduced pathogenic lipid uptake and clearance/sequestration. Moreover, it might improve cholesterol accumulation and augment toll-like receptor function in macrophages, which supported inflammatory responses. Accordingly, PCSK9 might show detrimental effects on immune host response and survival in sepsis. However, the exact roles of PCSK9 in the pathogenesis of sepsis are still not well defined. In this review, we summarized the literatures focusing on the roles of PCSK9 in sepsis. Our review provided an additional insight in the role of PCSK9 in sepsis, which might serve as a potential target for the treatment of sepsis.

Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall.

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low-density lipoprotein (LDL)-cholesterol levels by binding to the LDL-receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain-of-function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR-dependent or -independent mechanisms. More recently, several clinical trials have confirmed that anti-PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all-cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR-related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid-lowering therapy and disease prevention.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Not Induced in Artificial Human Inflammation and Is Not Correlated with Inflammatory Response.

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. However, knowledge about the role and kinetics of PCSK9 in human inflammation is currently insufficient. This study aimed to investigate the interaction between inflammation and lipid metabolism, including the possible role of PCSK9. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men received lipopolysaccharide (LPS) or placebo on two different study days after overnight fasting. Lipoproteins as well as PCSK9 were measured repetitively over 48 h. PCSK9 plasma concentrations were not induced by LPS infusion, and no correlation between PCSK9 plasma concentrations and the degree of inflammation could be identified. The observed low-density lipoprotein (LDL) response to inflammation was more complex than anticipated, especially in the very early phase after the inflammatory stimulus. Baseline concentrations of LDL, as well as high-density lipoprotein (HDL), correlated negatively with inflammatory response. Our data suggest that the lipoprotein response to inflammation is independent of PCSK9. The proposed elevations of PCSK9 and suspected correlations between PCSK9 levels and inflammatory response are not supported by our data. (This study has been registered at ClinicalTrials.gov under registration no. NCT03392701.).

Role of PCSK9 in the course of ejection fraction change after ST-segment elevation myocardial infarction: a pilot study.

AimsProprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low‐density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure‐related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging‐derived left ventricular ejection fraction (LVEF) after a first ST‐segment elevation myocardial infarction (STEMI).Methods and resultsWe prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ≥ II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = −0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002).ConclusionsIn patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months.

Pcsk9 9 Induces Vascular Calcification Under Uremic Conditions: In Vitro And In Vivo Study

Background and Aims: Vascular calcification represents a main risk factor of cardiovascular events in patients with chronic kidney disease (CKD). Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) levels correlates with the presence of calcific aortic valve stenosis and carriers of the PCSK9 R46L loss-of-function variant have a low calcific aortic valve stenosis. We investigated a possible role of PCSK9 on aortic calcification.

Age and Sex Specific Modulation of Serum Proprotein Convertase Subtilisin/kexin type 9 Levels in Rheumatoid Arthritis

Background/PurposeProprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that regulates cholesterol homeostasis by inducing posttranslational modification and lysosomal degradation of low‐density lipoprotein receptor (LDLR). However, the role of PCSK9 in dyslipidemia associated with rheumatoid arthritis (RA) is not well studied. The aim of this study was to examine how PCSK9 levels correlate with age [30–45; 46–60; and 61–80 years], sex, and RA disease, and with CD36, a major scavenger receptor targeted for proteasomal degradation by PCSK9.MethodsDe‐identified human RA serum samples (n=66; 33 female and 33 male) were obtained from patients diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and healthy, age and gender‐matched serum samples were used for evaluation. Serum levels of human PCSK9 and CD36 were determined using commercially available ELISA kits.ResultsThe mean (SD) age of healthy group [55.6 (11.2) years] and RA group [57.2 (10.4) years] was observed. Results of the ELISA showed that the serum levels of PCSK9 in RA group is reduced by ~10% (mean ± SEM; 231 ± 11.6 ng/ml vs. 205 ± 11.1 ng/ml; p&lt;0.14). Interestingly, our gender‐based analysis showed that the basal serum PCSK9 levels were around 30% higher in the healthy female group compared to the healthy male group (260 ± 15.9 ng/ml vs. 202 ± 15.4 ng/ml; p=0.01). Furthermore, from a disease perspective, we observed approximately 15% lower serum PCSK9 levels in female RA group (260 ± 15.9 ng/ml vs. 219 ± 14.4 ng/ml; p=0.078) compared to only a modest 5% decline in male RA group (202 ± 15.4 ng/ml vs. 191 ± 16.8 ng/ml; p=0.62) when compared to their respective gender control groups. Analysis of PCSK9 data based on age showed that while PCSK9 levels gradually decreased in healthy female group [274.4 ± 38.9 ng/ml in 30–45y range vs. 241 ± 20.7 ng/ml in 61–80y], we observed an accelerated decrease in serum PCSK9 levels in RA female group [278.5 ± 62.4 ng/ml in 30–45y range vs. 220 ± 19.2 ng/ml in 46–60y; p=0.14]. This suggests that PCSK9 levels rapidly decline with RA progression in aging females. Interestingly, the serum PCSK9 levels in both healthy and RA male groups showed declines at a later stage of life [61–80y range; p&lt;0.001], implicating that PCSK9 levels deplete in male groups, independent of RA disease pathogenesis. Serum CD36 levels in healthy female group were modestly low when compared to the serum levels in healthy male group [mean ± SEM; 1121 ± 164 pg/ml vs. 1280 ± 216 pg/ml; p&lt;0.562]. Interestingly, while the CD36 levels were around 30% higher in RA males compared to the healthy male controls, we observed a modest decrease in serum CD36 by 15–20% in RA females when compared to the healthy female controls.ConclusionOur findings provide evidence of the gender differences in serum PCSK9 levels and its modulation with age. Furthermore, it is speculated that an early decline in serum PCSK9 in female RA patients may contribute towards the establishment of RA in females.Support or Funding InformationWashington State University, Spokane, WAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.