PCSK9 and its Role in LDL Receptor Regulation Muscat, Oman - 9 February 2019
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1 PCSK9 and its Role in LDL Receptor Regulation Muscat, Oman - 9 February 2019 Professor Gilles Lambert, PhD LaboratoireInserm U1188 Universitéde la Réunion Faculté de Médecine Saint Denis de la Réunion, France. SAGLB.ALI G-PCS-1075 Date of preparation: August 2015
2 I The Discoveryof PCSK9
3 LipoproteinMetabolismand Atherosclerosis LDL clearance
4 The LDL Receptor 4
5 Familial Hypercholesterolemia(FH) Plasma Total Cholesterol > 8mM (3g/L) Tendon Xanthomas Corneal Arcus Xanthelasma Coronary Syndromes (Family) LDL Receptor 90% ApoB100 (LBD) 5% LDLR adaptor protein (ARH) < 0.1%
6 Two French Families With Autosomal Dominant Hypercholesterolemia Abifadel et al. (2003) Nature Genetics
7 PCSK9: gain of function mutations LDL-C S127R F216L D374Y D H N S SP pro-domain catalytic domain C-terminal domain
8 PCSK9 Expression IncreasesCirculatingLDL CholesterolLevelsin Mice Plasma Total Cholesterol (mg/dl) Ad-Null Ad-PCSK9 * * * Maxwell and Breslow (2004) Proc Natl Acad Sci USA Benjannet et al. (2004) J Biol Chem Park et al. (2004) J Biol Chem Lalanne et al. (2005) J Lipid Res Days post adenoviral infusion * p<0,05 vs. Ad-null
9 PCSK9: loss of function mutations D H N S SP pro-domain catalytic domain C-terminal domain LDL-C R46L Y142X C679X
10 Cardiovascular benefits of PCSK9 loss of function mutations No Nonsense Mutation (N=3278) th Percentile 88% reduction in the risk of CHD 12 Frequency (%) PCSK9 142x or PCSK9 679X (N=85) Plasma LDL-C in Black Subjects (mg/dl) Coronary Heart Disease (%) No Yes PCSK9 142x or PCSK9 679X Prospective study of plasma LDL-C levels and incidence of CHD according to the presence or absence of a PCSK0 142X or PCSK9 679X allele (N=3278) taken from a longitudinal, biracial cohort study designed to assess subclinical and clinical atherosclerosis (N=15792) Cohen J, et al. N Engl J Med 2006;354:
11 PCSK9 Knockout MiceHave DecreasedPlasma Cholesterol 125 Total Cholesterol (mg/dl) * 0 Control PCSK9-KO (-/-) * p<0,05 vs. Control Rashid et al. (2005) Proc Natl Acad Sci USA
12 Direct Relationship BetweenAtherosclerosisand PCSK9 Expression in Mice Plasma Cholesterol (mg/dl) Cholesteryl ester (µg/aorta) +80% % 1200 *** *** % *** -74% 5 *** PCSK PCSK ***P <0,001 vs. wild type (+) Denis M et al. (2012) Circulation
13 II The Biologyof PCSK9
14 PCSK9 ismainlyexpressedin and secretedfromthe liver PCSK9 mrna abundance in mouse tissues (normalized to 16S) Zaid et al. (2008) Hepatology
15 PCSK9: the enzyme (proprotein convertase) D H N S Endoplasmic Reticulum pro-domain catalytic domain C-terminal domain Golgi D H N S catalytic domain C-terminal domain pro-domain Secretion
16 PCSK9: the chaperone (binds to the LDLR) PCSK9 Catalytic domain LDLR EGFA domain CHRD Pro-domain Endocytosis Seidah NG, et al. Circ Res 2014;114:
17 PCSK9 targets the LDLR to the lysosome for degradation LDLR Endosome Merge PCSK9-LDLR Binding Kd=750±80nM (at ph 7.5) Kd= 10±1nM (at ph 5.5) LDLR Conformation Open (at ph 7.5) + PCSK9 Closed (at ph 5.5) alone Open (at ph 5.5) bound to PCSK9 Lambert et al. (2016) EurHeart J 37: SurdoPL, et al. EMBO Rep 2011;12:
18 PCSK9 reduces LDLR cell surface expression dose dependently MFI = median fluorescence intensity * p<0.05, ** p<0.01 vs. condition no PCSK9 (0) Lambert G, et al. (2014) J Am Coll Cardiol63: Thedrezet al. (2016) ArteriosclerThrombVasc Biol36:
19 PCSK9: a natural circulating inhibitor of the LDL receptor
20 III The StatinParadox
21 StatinsUpregulatethe Expression of the LDL Receptor 20% FCS 0,5% FCS 0,5% FCS + Mevastatin (fetal calf serum) Isotype 20% FCS LDLR 0,5% FCS Mevastatin 10 Mevastatin Median Fluorescence Intensity ** CellMedian surface expression Fluorescence Intensity Lambert et al. (2014) J Am Coll Cardiol
22 StatinsAlsoUpregulatethe Expression of PCSK9 Statins SREBP2 PCSK9 LDLR LDL-C SREBP2 = sterol regulatory element-binding protein 2
23 StatinsIncreaseCirculatingPCSK9 Levelsin cohorts 400 Mean PCSK9 (ng/ml) * 345 ** 352 ** Atorva 10 (n=449) Atorva 20 (n=449) Atorva 40 (n=447) Atorva 80 (n=399) Atorvastatin Dose * p<0,01 vs. 10mg, ** p<0,01 vs. 10, 20mg Arsenault et al. (2018) J Clin Lipidol
24 PCSK9 in Brief: PCSK9 is a natural circulating inhibitor of the LDLR. PCSK9 targets the receptor for degradation following endocytosis. PCSK9 and LDLR genes co-regulated by intracellular cholesterol content and statin treatment (mainly expressed in the liver). Targeting plasma PCSK9 is conceptually a promising approach to lower LDL-C levels in monotherapy as well as on top of statins.
25 PCSK9 inhibition withmabsin clinicaltrials reducesldlc by 60% on top of standard therapy Alirocumab Evolocumab Robinson JG et al. N EnglJ Med 2015;372: SabatineMS et al. N EnglJ Med 2015;372:
26 PCSK9 inhibition withmabsreducesmace In large outcomeclinicaltrials Primary Efficacy Endpoint: MACE ACC.18 Primary Endpoint MACE: CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization *Based on cumulative incidence HR 0.85 (95% CI 0.78, 0.93) P= ARR* 1.6% 31 CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% 0% Hazard ratio % (95% CI, ) P< Placebo 12.6% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization Evolocumab SabatineMS et al. N EnglJ Med 2217 Schwartz GG et al. N EnglJ Med 2018 Insert reference here 26
27 THANK YOU
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