Number Of Low Density Lipoprotein Receptors Research Articles

The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Gene Expression in a Cell-Free Transcription/Translation System.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.

Current Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review.

The effectiveness of immunotherapy for most cancer patients remains low, with approximately 10-30% of those treated surviving. Thus, much effort is being put into finding new ways to improve immune checkpoint therapy. Our review concludes that inhibition of proprotein convertase subtilisin/Kexin type 9 (PCSK9), which plays a critical role in regulating cholesterol metabolism, can cause movement of T cells toward tumors, with increased sensitivity to immune checkpoint therapies. We searched PubMed, NCBI, Scopus, and Google Scholar for the published articles without limitations on publication dates. We used the following terms: "PCSK9", "Cancer", "Immune Checkpoint", and "Cancer Prognosis" in the title and/or abstract. Our search initially revealed 600 records on the subject and stored them in the used databases under EndNote X8 management software. A total of 161 articles were selected and through a careful review, 76 were included in our research. We concluded that PCSK9 reduces the number of LDL receptors (LDL-R) on the cell surface, which is linked to its ability to regulate cholesterol levels in the body. Also, we discuss how suppressing PCSK9 leads to the MHC-1 accumulation on the surface of cancer cells, which results in T lymphocyte invasion. Finally, we believe that inhibiting PCSK9 may be an effective strategy for improving cancer immunotherapy.

Phytochemical screening and evaluation of glucose-6-phosphate dehydrogenase activity of fermented honey-garlic in hypothyroidism rats

Introduction: Hypercholesterolemia is an indicator of atherosclerosis in blood vessels and is currently a top priority in overcoming health problems, especially non-communicable diseases in developed and developing countries. Thyroid hormones regulate various metabolic processes in the body including synthesis, mobilization, and lipid degradation. A lack of thyroid hormone in the body or called hypothyroidism will decrease the number of LDL receptors in the liver. This causes an increase in plasma LDL levels which also increases total cholesterol levels. Despite the lack of study, Fermented Honey-Garlic (FHG) is now widely developed for its high antioxidant activity. This study aims to determine the content of bioactive compounds in FHG by qualitative secondary metabolite testing and GC-MS analysis and to evaluate the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in rats with hypothyroidism. Method: Rats were grouped into 6 groups: positive control group induced by propylthiouracil (PTU) with a dose of 20 mg/day, negative control treated with distilled water, treatment group with a dose of FHG 0.2 g/kg BW (P1), treatment group with a dose of FHG 0.5 g/kg BW (P2), treatment group with a dose of FHG 1 g/kg BW (P3) and standard drug Simvastatin group with the dose 0,18 mg/day/200 g BW. Results: Results showed that FHG contained flavonoid compounds, alkaloids, tannins, and saponins, and statistical results showed that the significance value for G6PD activity was 0.014 (P<0.05). Conclusion: Therefore, it can be concluded that FHG administration yields a significant effect on G6PD levels.

Inclisiran-A Revolutionary Addition to a Cholesterol-Lowering Therapy.

Hypercholesterolemia plays a crucial role in the development of atherosclerosis, but it remains an undertreated and underdiagnosed disease. Taking into consideration the high prevalence of lipid disorders, long duration of the asymptomatic course of the disease, life-threatening complications resulting from inaccurate therapy, and stringent treatment goals concerning LDL cholesterol level in the prevention of cardiovascular events, novel lipid-lowering therapies have been introduced in the last few years. In this article, a drug belonging to the group of small interfering RNA (siRNA) called inclisiran is described. It is a novel molecule that increases the number of LDL receptors (LDLRs) on the surface of hepatic cells by preventing the formation of proprotein convertase subtilisin/kexin type 9 (PCSK9) responsible for the degradation of LDLRs. With great potential for lowering plasma LDL cholesterol level, high liver specificity, comfortable dosing regimen, and good tolerance without significant adverse effects, it could play an important part in future hypolipemic therapies.

Abstract 10882: Homozygous Familial Hypercholesterolemia: Luck Meets Opportunity Meets Knowledge

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an inherited autosomal co-dominant disorder characterized by severely elevated circulating low-density lipoprotein (LDL). Monoclonal antibodies are now a treatment focus. Inhibition of proprotein convertase subtilisin kexin type 9 (PCSK9) increases the number of LDL receptors. Inhibition of angiopoietin-like 3 (ANGPTL3) inhibitor is associated with hypolipidemia and reduced risk of cardiovascular disease. We present the case of one of the oldest living patients with HoFH. Case Description: The patient is a 67-year-old black woman diagnosed with corneal arcus senilis and xanthomas at the age of 11, with total cholesterol (TC) levels >1000 mg/dL. At age 12, she underwent a partial ileal bypass (PIB) that lowered her TC by 39%. At age 32, she began statin therapy (Lovastatin, intensified to Atorvastatin at age 43). Despite concomitant dietary changes, her LDL levels remained elevated (>400 mg/dL). At age 34, multivessel coronary artery disease was detected and she initiated lipoprotein apheresis. Her LDL-C was reasonably well-controlled over the 20 years on LDL apheresis and high intensity statin therapy. Combined therapy with PCSK9 inhibitors (Evolocumab at age 61, replaced by Alirocumab at age 67) and ANGPTL3 inhibitor Evinacumab (age 67) lowered her LDL-C significantly. Genetic analysis confirmed two LDLR mutations: c.1846-1G>A and c.907C>T. Conclusion: Elevated cholesterol levels are linked to a higher risk of premature myocardial infarction and stroke. We report a case of HoFH with successful lowering of LDL levels on dual antibody and high intensity statin therapy along with PIB. Unlike PCSK9 inhibitors, ANGPTL3 inhibitors work independently of LDLRs by stimulating lipoprotein & endothelial lipase. This case offers insight into early surgical and combination drug therapy in HoFH and describes one of the longest living patients with HoFH illustrating treatment evolution.

PCSK-9 Inhibitors

Hyperlipidemia (elevated levels of LDL-C) is a well-known risk factor of cardiovascular diseases (CVD). Statins are well known and proven drugs for the lipid management of those who are at elevated risk for developing CVD events1. However, the patients who do not tolerate statin therapy, develop any cardiovascular disease despite maximal tolerated statins, or with severe hypercholesterolemia i.e familial hypercholesterolemia had limited options. Recently the Food and Drug Administration (FDA) approved medications (PCSK-9 inhibitors) which act on a novel pathway to reduce LDL-C levels in blood.
 HOW DO PCSK9 INHIBITORS WORK?
 PCSK-9 inhibitors (monoclonal antibodies) act on proprotein convertase subtilsin-kexin type 9 (PCSK9) and inactivate it. The PCSK9 protein has strongly inhibit recycling of the LDL receptor (LDLR). It is predominantly produced by hepatocytes, with other sites being kidneys and intestines.2,3 On the surface of liver cell, LDL binds to its receptor called LDLR. This LDL-LDLR complex is then internalized, after which the LDLR is recycled back to the cell surface up to 150 times.4 The role of PCSK9 protein is to bind the LDLR on the surface of the hepatocyte, causing internalization and degradation of the LDL receptors in the lysosomes, this process in turn reduces the number of LDL receptors on the cell surface. So, by Inhibition of PCSK9, number of available LDL receptors on the cell surface is increased and uptake of LDL?C into the cell is augmented. PCSK9 inhibition thus offers a novel therapeutic approach for the lowering of LDL-C levels.5 Currently, the only FDA?approved PCSK9 inhibitors are two human monoclonal antibodies which bind extracellular PCSK9: alirocumab6 and evolocumab.7
 FDA APPROVAL OF PCSK9 INHIBITORS AND REDUCTION IN LDL-C:
 Alirocumab (Praluent) was approved by FDA in 2015 for adult patients with heterozygous familial hypercholesterolemia or for patients with clinically significant atherosclerotic CVD requiring additional LDL lowering despite being on diet control and maximal tolerated statin therapy. Alirocumab’s long-term safety and efficacy was evaluated in ODYSSEY trials which include CHOICE I, CHOICE II, OLE, LONG TERM, COMBO I, COMBO II, FH I, FH II, HIGH FH, MONO, ALTERNATIVE, OPTIONS I and OPTIONS II. There was a 65% LDL-C levels reduction in a dose dependent fashion at maximal doses.8
 FDA also approved Evolocumab (Repatha) in 2015 for use in adult patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or clinical atherosclerotic CVD requiring additional lowering of LDL cholesterol despite being on a controlled diet and maximally-tolerated statin therapy. PROFICIO (Program to reduce LDL-C and cardiovascular outcomes following inhibition of PCSK9 in different populations) phase III 14 trials were designed to evaluate efficacy and long-term safety of evolocumab. Every two-week regimen reduced LDL-C levels by up to 65% as compared to approximately 50% with every 4-wk regimen.
 DOSAGE:
 Alirocumab (Praluent) is given in dosage of 75-150 mg every two weeks while Evolocumab (Repatha) is given in dosage of 140 mg every two weeks or 420 mg monthly
 ADVERSE EFFECTS AND LIMITATIONS
 The most common adverse effects observed with Alirocumab include nasopharyngitis, erythema, itchiness, swelling, pain or tenderness, influenza, urinary tract infection, diarrhea, bronchitis, myalgia, muscle spasms, sinusitis and cough. The most common adverse effects of Evolocumab include nasopharyngitis, upper respiratory tract infection, back pain and nausea. A small percentage (2.4%) of some serious cardiac adverse events were also noted which include palpitations, angina pectoris, and ventricular premature contractions.
 Some common limitations of PCSK9 inhibitors are that they are very expensive, not readily available in our country and are required in injection form.
 CONCLUSION:
 PCSK9 inhibitors are exciting and very welcome new treatment option for patients who require treatment for their elevated LDL-C levels. They have proven to be very effective in reducing LDL-C levels and in-turn reducing ASCVD events

Insight into the Evolving Role of PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

Naturalne inhibitory PCSK9 — przegląd substancji o możliwym wpływie na PCSK9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein discovered in 2003 and playing an important role in lipoprotein metabolism. The main function of PCSK9 is to regulate the number of low-density lipoprotein (LDL) receptors on the surface of hepatocytes. The biological effect of PSCK9 is to reduce the number of LDL receptors on the surface of hepatocytes, which reduces their ability to take up LDL lipoproteins. PCSK9 inhibitors such as alirocumab, evolocumab or inclisiran are a new, very effective method of lipid-lowering therapy. Recently, a number of naturally derived compounds have been identified that are characterized by the ability to reduce the activity of PCSK9. These compounds are among the alkaloids, polyphenols, sterols, stanols, vegetable proteins and other nutrients and may find application in supporting the pharmacotherapy of lipid disorders.

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.

Inclisiran in dyslipidemia.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Hypercholesterolemia has been shown to be one of the most important risk factors for CVD. Statins are currently the standard of care for the management of hypercholesterolemia. However, certain patients on statin therapy fail to achieve the desired low-density lipoprotein cholesterol (LDL-C) goals or are intolerant to statins due to side effects (mostly myalgias). The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the subsequent development of PCSK9 inhibitors provided another route to lower LDL-C levels by increasing recycling of LDL receptors (LDLR) in the hepatocytes. More recently, inclisiran, a small interfering RNA (siRNA) molecule, which increases the number of LDLR in the hepatocyte membranes by halting the transcription of PCSK9, has emerged as a novel promising agent for the management of hypercholesterolemia. Inclisiran received marketing authorization in the European Union in December 2020 for use in adults with primary hypercholesterolemia or mixed dyslipidemia. This review aims to focus on the role of inclisiran in the management of hypercholesterolemia.

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia

Rationale:Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events.Patient concerns:We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia.Diagnosis:Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [exon 6:c.902A>G:p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [exon1:c.137 G>T:p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [c.902A>G:p.(Asp301Gly); c.1646G>T:p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [(PCSK9:exon1:c.137G>T:p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter.Interventions:The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control.Outcomes:To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication.Lessons:Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations (LDLR-PCSK9) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.

PCSK9 Inhibitors: From Nature’s Lessons to Clinical Utility

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. To describe the origins of PCSK9 inhibitors and their current use in clinical practice. We performed a narrative review of the PCSK9 inhibitor class of drugs. Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

Strategies to prevent cleavage of the linker region between ligand-binding repeats 4 and 5 of the LDL receptor

A main strategy for lowering plasma low-density lipoprotein (LDL) cholesterol levels is to increase the number of cell-surface LDL receptors (LDLRs). This can be achieved by increasing the synthesis or preventing the degradation of the LDLR. One mechanism by which an LDLR becomes non-functional is enzymatic cleavage within the 10 residue linker region between ligand-binding repeats 4 and 5. The cleaved LDLR has only three ligand-binding repeats and is unable to bind LDL. In this study, we have performed cell culture experiments to identify strategies to prevent this cleavage. As a part of these studies, we found that Asp193 within the linker region is critical for cleavage to occur. Moreover, both 14-mer synthetic peptides and antibodies directed against the linker region prevented cleavage. As a consequence, more functional LDLRs were observed on the cell surface. The observation that the cleaved LDLR was present in extracts from the human adrenal gland indicates that cleavage of the linker region takes place in vivo. Thus, preventing cleavage of the LDLR by pharmacological measures could represent a novel lipid-lowering strategy.

Statement for Appropriate Clinical Use of PCSK9 Inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that promotes the degradation of LDL receptors. Evolocumab (Repatha®), a recombinant human IgG2 antibody, and alirocumab (Praluent ®), a recombinant human IgG1 antibody, are new types of drug that lower blood LDL cholesterol (LDL-C) by inhibiting PCSK9 and increasing the number of LDL receptors on the surface of hepatocytes. In combination with statins, PCSK9 inhibitors achieve a very strong LDL-C lowering effect making them a powerful option for patients with insufficient LDL-C management with existing drugs. However, the drugs are expensive. Therefore, from the viewpoints of medical and medical economics, it is an urgent issue to identify the types of patients who really need them and would be benefitted greatly from their use. In this regard, the Japan Atherosclerosis Society would like to express its views in accordance with the JAS Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases 20171).

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

Evaluation of plasma PCSK9 concentrations, transcript of LDL receptor, as well as the total number of monocyte LDL receptors in acute coronary syndrome patients

Before our study, there were no data concerning complex evaluation of: plasma PCSK9 concentrations, transcript LDL receptor (LDLR), as well as the total amount of monocytes' LDLR in acute coronary syndrome (ACS) patients. PCSK9 levels in a few cohort studies were found to correlate with the number of white blood cells (WBC) or platelets (PLT). The study aims to evaluate PCSK9-LDLR concentrations, as well as to find any association between PCSK9 and WBC or PLT. The study group included 95 consecutive patients with acute myocardial infarction, in whom angiography/angioplasty of the culprit vessel was performed. The control group consisted of 10 healthy young volunteers. Thirty patients from the studied group were qualified for further percutaneous revascularization after 3 months. Laboratory tests were performed using commercially available kits. LDLR expression on monocyte surface was measured by flow cytometry, but the mRNA level for LDLR was established by real time polymerase chain reaction. The PCSK9 plasma concentration was measured by ELISA kits. Higher concentration of PCSK9 and amount of LDLR on monocytes surface were observed in patients with ACS compared with healthy young volunteers (number of LDLRs on monocytes [reaction units] 10.8 ± 9.6 vs. 41.8 ± 11.8, p < 0.001, PCSK9 [ng/mL] 295.4 ± 76.4 vs. 213 ± 63.2, p < 0.001). A similar relationship was observed after application of 3-month intensive lipid-lowering therapy in patients with ACS (n = 30, PCSK9 [ng/mL] 281.1 ± 59.5 vs. 358.5 ± 74.7, p < 0.001, LDLR transcript [reaction units] 0.6 ± 0.32 vs. 1.87 ± 0.24, p < 0.001, number of LDLRs on monocytes [reaction units] 5.9 ± 3.1 vs. 22.3 ± 3.8, p < 0.001). There were no significant differences in levels of PCSK9, LDLR between patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI). There was no relation of the PCSK9 with WBC as well as with PLT. We observed significantly higher concentration of PCSK9, and significantly higher levels of mRNA LDLR transcript in patients with ACS compared with healthy young volunteers. A similar pattern was observed after 3 months of intensive statin therapy among patients with ACS. There were no differences in these parameters between patients with STEMI vs. NSTEMI. The results of the study require confirmation in a larger population of patients.

Role of lipoproteins and proprotein convertase subtilisin/kexin type 9 in endotoxin clearance in sepsis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a recent high-impact cardiovascular intervention aimed at reducing low-density lipoprotein (LDL) cholesterol levels. Notably, pathogen lipids are also carried in lipoprotein particles and are cleared by hepatocyte LDL receptors. Therefore, the role of PCSK9 in sepsis is reviewed. Endogenous PCSK9 decreases clearance of LDL cholesterol by decreasing the number of LDL receptors on hepatocytes. Similarly, PCSK9 decreases clearance of pathogen lipids, such as endotoxin, carried in LDL. Pathogen lipids, such as lipopolysaccharide (LPS) from gram-negative organisms or lipoteichoic acid from gram-positive organisms, are carried in high-density lipoprotein, LDL, and very low-density lipoprotein particles. Transfer proteins that handle pathogen lipids (e.g., LPS binding protein) are homologous to transfer proteins that handle cholesterol (e.g., phospholipid transfer protein, cholesterol ester transfer protein). Reduction in PCSK9 function results in increased LPS clearance, a decreased inflammatory response, and improved clinical outcomes in mice. PCSK9 inhibition improves survival in septic mice. Similarly, humans who carry loss-of-function variants of the PCSK9 gene have increased survival in sepsis. PCSK9 inhibition may be a useful strategy to increase pathogen lipid clearance in the treatment of patients with sepsis.

An evaluation of alirocumab for the treatment of hypercholesterolemia

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipoprotein metabolism, mainly by modulating LDL receptor activity. Alirocumab is a fully human IgG1 monoclonal antibody that binds PCSK9, increases the number of LDL receptors and decreases the levels of LDL cholesterol. The efficacy of alirocumab has been evaluated in more than 6000 subjects with primary hypercholesterolemia; in Phase III trials, alirocumab consistently reduced LDL-cholesterol up to 62% with every 2 weeks dosing compared with placebo and up to 36% compared with ezetimibe. Two doses, 75 and 150 mg, have been developed to propose a tailored approach in the treatment of hypercholesterolemic patients not controlled by maximally tolerated lipid-lowering therapy. Alirocumab was generally well-tolerated, with an acceptable safety profile. The ongoing ODYSSEY OUTCOMES trial will provide definitive evidence on the effect of alirocumab on cardiovascular morbidity and mortality and complementary data on the long-term safety and tolerability. Moreover, a cost–effectiveness analysis would be useful to determine the appropriate price of alirocumab.

New developments in atherosclerosis: clinical potential of PCSK9 inhibition.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted 692-amino acid protein that binds surface low-density lipoprotein (LDL) receptor (LDLR) and targets it toward lysosomal degradation. As a consequence, the number of LDLRs at the cell surface is decreased, and LDL-cholesterol (LDL-C) clearance is reduced, a phenomenon that is magnified by gain-of-function mutations of PCSK9. In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance. This provides the rationale for targeting PCSK9 in hypercholesterolemic subjects as a means to lower LDL-C levels. Monoclonal antibodies (mAbs) against PCSK9 that block its interaction with the LDLR have been developed in the past decade. Two companies have recently received the approval for their anti-PCSK9 mAbs by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Regeneron/Sanofi, with alirocumab (commercial name – PRALUENT®) and, Amgen with evolocumab (commercial name – Repatha™). The introduction of anti-PCSK9 mAbs will provide an alternative therapeutic strategy to address many of the unmet needs of current lipid-lowering therapies, such as inability to achieve goal LDL-C level, or intolerance and aversion to statins. This review will focus on the kinetics of PCSK9, pharmacokinetics and pharmacodynamics of anti-PCSK9 mAbs, and recent data linking PCSK9 and anti-PCSK9 mAbs to cardiovascular events. Moreover, it will highlight the unanswered questions that still need to be addressed in order to understand the physiologic function, kinetics, and dynamics of PCSK9.

Monensin Enhances the Binding of LDL to Human Hepatocyte-Like C3A Cells without Increasing the Number of LDL Receptors at the Plasma Membrane

Monensin Enhances the Binding of LDL to Human Hepatocyte-Like C3A Cells without Increasing the Number of LDL Receptors at the Plasma Membrane