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.

scholarly journals Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature

2019 ◽  
Author(s):  
Sara Oppi ◽  
Stefanie Nusser-Stein ◽  
Przemyslaw Blyszczuk ◽  
Xu Wang ◽  
Anne Jomard ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Myeloid Cell ◽  
Foam Cell Formation ◽  
Low Density ◽  
Enhanced Expression ◽  
Atherosclerosis Development

Abstract Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. Conclusions Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1–PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.

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.

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.

Effects of PCSK9 Inhibitors on Other than Low-Density Lipoprotein Cholesterol Lipid Variables

2017 ◽  
Vol 23 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Theodosios D. Filippatos ◽  
Anastazia Kei ◽  
Christos V. Rizos ◽  
Moses S. Elisaf
Keyword(s):  
Cardiovascular Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
The Other ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors ◽  
Beneficial Effects

Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, but other lipid variables such as triglycerides (TRGs), high-density lipoprotein cholesterol (HDL-C) and lipoprotein a [Lp(a)] also affect cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-C concentration but also modestly improve the concentrations of TRGs and HDL-C and more robustly decrease Lp(a) levels. The review presents the associated mechanisms of the beneficial effects of PCSK9 inhibitors on the other than LDL-C lipid variables, including the effects on lipid/apolipoprotein secretion and clearance and the heteroexchange between lipoproteins, as well as the possible effects on other variables involved in lipid metabolism such as sortilin. Proprotein convertase subtilisin/kexin type 9 inhibitors improve the overall lipid profile, and these beneficial effects may play a role in the reduction of cardiovascular risk.

Abstract 129: Effects of a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Normal Subjects

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Gissette Reyes-Soffer ◽  
Marianna Pavlyha ◽  
Colleen Ngai ◽  
Paul Ippolito ◽  
Stephen Holleran ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Phase 1 ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Normal Subjects ◽  
New Drugs ◽  
Low Density ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors

Background: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are promising new drugs for the treatment of hypercholesterolemia. They inhibit the binding of PCSK9 to the low density lipoprotein (LDL) receptor that, in turn, decreases lysosomal degradation of LDL receptors and increases their numbers on the cell surface. In Phase 2/3 studies, alirocumab significantly lowered plasma levels of LDL-cholesterol (C) and apolipoprotein B (apoB). The mechanism underlying the LDL-C lowering effects of PCSK9 inhibition has not been reported. Method: We enrolled 10 healthy volunteers (4 male, 6 female), into a Phase 1, placebo-controlled, single-blind, single-sequence study to examine the effects of alirocumab, 150 mg administered subcutaneously every two weeks, on lipid and lipoproteins levels and the metabolism of apoB in very low density (VLDL), intermediate density (IDL) and LDL. Subjects received 2 doses of placebo followed by 5 doses of alirocumab. At the end of each treatment period, fasting lipids and lipoprotein levels were measured, and stable isotope studies of the apoB turnover in VLDL, IDL and LDL were performed. Results: Alirocumab significantly reduced plasma levels of total-C by 37% (178.4±34 to 112.7±29 mg/dL), LDL-C by 59% (110.2±25 to 45.5±26 mg/dL), and apoB by 51% (93.6±25 to 45.5±13 mg/dL) compared to placebo. Plasma triglycerides (TG) and HDL-C did not change. Levels of LDL-C, LDL-TG, and LDL-apoB fell by 55.8±10%, 33.9±13%, and 56.0±11%, respectively (all p<0.0001), on alirocumab. The reductions in LDL apoB were explained by a dramatic increase in the fractional clearance rate (FCR) of LDL apoB from 0.50±0.18 on placebo to 1.02±0.35 pools/day on alirocumab (p<0.001) and a trend toward lower LDL apoB production rates on alirocumab (15.1±4.6 vs 12.9±3.3 mg/kg/day; p=0.10). Levels of IDL-C, IDL-TG and IDL-apoB were also reduced significantly and there was a trend toward an increase in IDL apoB FCR on alirocumab (placebo: 9.2±4 vs alirocumab: 10.8±3 pools/day; p=0.06). Additional kinetic parameters will be presented at the meeting. Summary: Alirocumab treatment significantly reduced the levels of IDL and LDL, and these changes were due to increases in the FCRs of these lipoproteins, particularly LDL.

scholarly journals Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol

2021 ◽  
Vol 8 ◽  
Author(s):  
Chandni Bardolia ◽  
Nishita Shah Amin ◽  
Jacques Turgeon
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Drug Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
New Drugs ◽  
Lipoprotein Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibitors

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia.

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