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

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Matthias Wolfgang Heinzl ◽  
Michael Resl ◽  
Carmen Klammer ◽  
Margot Egger ◽  
Benjamin Dieplinger ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
Innate Immune ◽  
Proprotein Convertase ◽  
Overnight Fasting ◽  
Lipoprotein Response ◽  
Kinetics Of

ABSTRACT 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.)

scholarly journals Abnormally expressed miR-23b in Chinese Mongolian at high cardiovascular risk may contribute to monocyte/macrophage inflammatory reaction in atherosclerosis

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Li-ping He ◽  
Xing-sheng Zhao ◽  
Le-ping He
Keyword(s):  
Cardiovascular Risk ◽  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Cardiovascular Risk ◽  
Peripheral Blood Mononuclear

Background: The prevalence of coronary heart disease (CHD) appears to be high among Chinese Mongolians. MiR-23b has been proven to play a key role in atherosclerosis. The expression and role of miR-23b in the Mongolians at high cardiovascular risk were explored in the present study. Methods: Forty cases of blood samples from the Mongolians at high cardiovascular risk were enrolled in the present study. The expression of miR-23b was quantified by quantitative real-time PCR. To induce monocytes differentiation into macrophages, HP-1 cells were cultured with phorbol 12-myristate 13-acetate. The level of inflammatory markers was determined by the enzyme-linked immunosorbent assay. The interaction between miR-23b and A20 was explored by the dual luciferase reporter assay. Results: The expression of miR-23b in the Mongolian at high cardiovascular risk was higher than that in healthy Mongolian volunteers. Decrease in ATP-binding cassette transporter A1 caused by miR-23b is responsible for TC accumulation in the Mongolian at high cardiovascular risk. MiR-23b enhanced the oxidized low-density lipoprotein (oxLDL)-induced inflammatory response of THP-1 derived macrophage. MiR-23b regulated nuclear factor-κB (NF-κB) pathway through targeting A20. MiR-23b mediated oxLDL-induced inflammatory response of peripheral blood mononuclear cell in the Mongolian at high cardiovascular risk. Conclusion MiR-23b enhanced oxLDL-induced inflammatory response of macrophages in the Mongolian at high cardiovascular risk through the A20/NF-κB signaling pathway, and thus contributing to atherosclerosis.

scholarly journals Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia

2011 ◽  
Vol 121 (9) ◽  
pp. 397-403 ◽  
Author(s):  
Martijn C.G.J. Brouwers ◽  
Marleen M.J. van Greevenbroek ◽  
Jason S. Troutt ◽  
Angela Bonner Freeman ◽  
Ake Lu ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Significant Rise ◽  
Low Density ◽  
Proprotein Convertase ◽  
Once Daily ◽  
Heritable Trait ◽  
The Relationship

The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)–apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)–apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67–84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.

Abstract 437: Lipoprotein(a) Internalization in HepG2 Cells is Regulated by Proprotein Convertase Subtilisin Kexin Type 9 Through the Low-Density Lipoprotein Receptor

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Rocco Romagnuolo ◽  
Nabil G Seidah ◽  
Marlys L Koschinsky
Keyword(s):  
Heavy Chain ◽  
Hepg2 Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Proprotein Convertase ◽  
Human Hepatoma Cells ◽  
Lipoprotein A ◽  
Clathrin Heavy Chain

Elevated levels of lipoprotein(a) (Lp(a)) have been identified as an independent and causal risk factor for coronary heart disease. Lp(a) consists of an LDL-like moiety covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). The mechanism by which Lp(a) is catabolized is currently unknown, but may form the basis for the development of drug therapy to reduce high levels of plasma Lp(a). Although the role of the LDL receptor (LDLR) in Lp(a) catabolism is controversial, recent evidence has shown that Lp(a) levels are significantly reduced with an antibody against proprotein convertase subtilisin kexin type 9 (PCSK9) in patients with hypercholesterolemia receiving statin therapy. Therefore, we explored the role of PCSK9 in Lp(a)/apo(a) internalization by hepatic cells. Lp(a) or apo(a) internalization is significantly reduced in HepG2 (human hepatoma) cells either by overexpressing PCSK9 or by treatment with purified PCSK9. The ability of Lp(a) and apo(a) to be internalized was significantly reduced in the presence of the lysine analogue, ε-ACA, indicating lysine-dependent interactions with cellular receptors. Mutation of the strong lysine binding site in a recombinant apo(a) variant resulted in a reduced ability to be internalized. While LDL can bind to PCSK9 and inhibit its ability to degrade the LDLR, we found that Lp(a) lacked these properties. Interestingly, overexpressing the LDLR on HepG2 cells significantly increased the ability of Lp(a) to be internalized, an effect that was partially reduced by the addition of PCSK9. This indicates a potential key role for the LDLR in regulating Lp(a) catabolism. Furthermore, knockdown of clathrin heavy chain resulted in a significant decrease in apo(a) internalization and apo(a) internalization was not further reduced by pre-treatment of PCSK9 in the context of clathrin heavy chain knockdown. Treatment of HepG2 cells with a lysosomal inhibitor, but not a proteosomal inhibitor, resulted in accumulation of Lp(a) in HepG2 cells indicating that Lp(a) is potentially targeted for degradation through lysosomes. Taken together, these results indicate that Lp(a)/apo(a) uptake can be regulated in HepG2 cells by PCSK9 and the LDLR through clathrin-mediated endocytosis and lysosomal degradation.

scholarly journals Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

2019 ◽  
Vol 115 (3) ◽  
pp. 510-518 ◽  
Author(s):  
Nabil G Seidah ◽  
Annik Prat ◽  
Angela Pirillo ◽  
Alberico Luigi Catapano ◽  
Giuseppe Danilo Norata
Keyword(s):  
Monoclonal Antibodies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Loss Of Function ◽  
Proprotein Convertase ◽  
Innovative Strategies ◽  
Density Lipoprotein Receptor ◽  
Low Levels

Abstract Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2–4 weeks, they trigger a ∼60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in ∼50–60% LDL-C lowering that lasts up to 6 months (Phases II–III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.

Inhibition of cholesterogenesis decreases hepatic secretion of apoB-100 in normolipidemic subjects.

1997 ◽  
Vol 273 (3) ◽  
pp. E462 ◽  
Author(s):  
G F Watts ◽  
R P Naoumova ◽  
J M Kelly ◽  
F M Riches ◽  
K D Croft ◽  
...  
Keyword(s):  
De Novo ◽  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
Mevalonic Acid ◽  
Normal Subjects ◽  
Gas Chromatography Mass Spectrometry ◽  
Low Density ◽  
Cholesterol Ratio ◽  
Kinetics Of

We examined the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of very low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in 13 normolipidemic men in a placebo-controlled crossover study. Simvastatin significantly decreased the plasma concentrations of low-density lipoprotein (LDL) cholesterol by 36%, triglycerides by 26%, mevalonic acid by 34%, and lathosterol by 32%. Hepatic secretion of VLDL apoB was measured using a primed constant intravenous infusion of [1-13C]leucine with monitoring of isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional turnover rate was derived using a monoexponential function. Simvastatin decreased VLDL apoB pool size by 53% and the hepatic secretion rate of VLDL apoB by 46% but did not significantly alter its fractional catabolism. The change in hepatic VLDL apoB secretion was significantly and independently correlated with changes in plasma mevalonic acid and lathosterol concentrations and the lathosterol-to-cholesterol ratio. The data support the hypothesis that the rate of de novo cholesterol synthesis directly regulates the hepatic secretion of VLDL apoB in normal subjects.

scholarly journals Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tharini Sivasubramaniyam ◽  
Jiaqi Yang ◽  
Henry S. Cheng ◽  
Alexandra Zyla ◽  
Angela Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Whole Body ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Atherosclerosis Treatment ◽  
Deficient Mice

AbstractInflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1−/−Apoe−/−). After 21 weeks of atherogenic diet, Dj1−/− Apoe−/−mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

scholarly journals The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Atherosclerosis Development

2019 ◽  
Vol 5 (5) ◽  
pp. 112-120 ◽  
Author(s):  
A. Chaulin ◽  
L. Karslyan ◽  
A. Aleksandrov ◽  
A. Mazaev ◽  
E. Grigorieva ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
New Drugs ◽  
Low Density ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Residual Cardiovascular Risk ◽  
Promising Therapeutic Target ◽  
Atherosclerosis Development

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Statins are the most widely used therapy for patients with hyperlipidemia. However, a significant residual cardiovascular risk remains in some patients even after maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new promising therapeutic target for decreasing LDL-C. PCSK9 reduces LDL intake from circulation by enhancing low-density lipoprotein receptors (LDLR) degradation and preventing LDLR recirculation to the cell surface. In addition to examining the functional role of PCSK9, this review also discusses new drugs for the treatment of hyperlipidemia — PCSK9 inhibitors.

The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats

1997 ◽  
Vol 77 (04) ◽  
pp. 710-717 ◽  
Author(s):  
Marieke E van der Kaaden ◽  
Dingeman C Rijken ◽  
J Kar Kruijt ◽  
Theo J C van Berkel ◽  
Johan Kuiper
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Single Chain ◽  
Liver Uptake ◽  
Type Plasminogen Activator ◽  
Parenchymal Liver ◽  
Urokinase Type Plasminogen Activator ◽  
Density Lipoprotein Receptor

SummaryUrokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E.coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA in rats. A preinjection of the LRP inhibitor GST-RAP reduced the maximal liver uptake of 125I-rscu-PA at 5 min after injection from 50 to 30% of the injected dose and decreased the clearance of rscu-PA from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10% of the liver uptake, respectively. The reduction in liver uptake of rscu-PA by the preinjection of GST-RAP was caused by a 91 % and 62% reduction in the uptake by parenchymal and Kupffer cells, respectively. In order to investigate the part of rscu-PA that accounted for the interaction with LRP, experiments were performed with a mutant of rscu-PA lacking residues 11-135 (= deltal25- rscu-PA). Deletion of residues 11-135 resulted in a 80% reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for respectively 60, 33 and 7% of the liver uptake of 125I-deltal25-rscu-PA. Preinjection of GST-RAP completely reduced the liver uptake of delta 125-rscu-PA and reduced its clearance to 0.79 ml/min. Treatment of isolated Kupffer cells with PI-PLC reduced the binding of rscu-PA by 40%, suggesting the involvement of the urokinase-type Plasminogen Activator Receptor (u-PAR) in the recognition of rscu-PA. Our results demonstrate that in vivo LRP is responsible for more than 90% of the parenchymal liver cell mediated uptake of rscu-PA and for 60% of the Kupffer cell interaction. It is also suggested that u-PAR is involved in the Kupffer cell recognition of rscu-PA.

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