Novel Reduction of PCSK9 Expression: Mechanistic Insights into the Anti-Atherosclerotic & Hypolipidemic Effects of Heat Shock Protein 27
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1 Novel Reduction of PCSK9 Expression: Mechanistic Insights into the Anti-Atherosclerotic & Hypolipidemic Effects of Heat Shock Protein 27 Ed O Brien, Jean-Claude Bakala-N Goma, Chunhua Shi Cumming School of Medicine ermobrie@ucalgary.ca
2 Heat Shock Protein 27 (HSP27) Traditionally viewed as an intracellular chaperone protein Estrogens increase synthesis & secretion (exosomes) Extracellular levels are inversely related to atherosclerosis Anti-atherogenic effects include: anti-apoptosis, antiinflammatory, lipid lowering (serum / plaque), etc. Signal from the outside in via TLR4, etc. Emerging role of anti-hsp27 auto-antibodies
3 Heat Shock Protein-27 Expression Diminishes as Atherosclerosis Progresses Normal Atherosclerosis Movat VWF8 Movat αsma Lumen Lumen Intima HSP27 αsma Media HSP27 Plaque Media Miller et al. Arterioscler Thromb Vasc Biol. 25; 25:e1-e14
4 Will HSP27 Over-expression (HSP27 o/e ) Protect Atherosclerosis-prone ApoE -/- Mice? X HSP27 o/e apoe -/- (Atherosclerosis-prone) HSP27 o/e apoe -/- High fat diet: for 4 wks (ACUTE) or 12 wks (CHRONIC) Analysis: lesion size, plaque composition, serum HSP27 and cholesterol levels Rayner et al., Circ Res 28 Cuerrier CM et al., PLoS ONE 213
5 HSP27-mediated Athero-Protection: Acute & Chronic Murine Experiments.8 24% Aortic Sinus Lesion Area (Mean ± SD, mm 2 ) % P <.1 NS 39% P <.1 P <.1. WT 27o/e WT 27o/e WT 27o/e WT 27o/e Female Male Female Male 4 wk-high Fat Diet 12 wk-high Fat Diet Rayner et al., Circ Res 28 Cuerrier CM et al., PLoS ONE 213
6 HSP27 Over-Expression Reduces Arterial Cholesterol Apo E -/- ApoE -/- HSP27 o/e Female Male Filipin stain for free cholesterol Rayner et al., Circ Res, 28 Cuerrier CM et al., PLoS ONE 213
7 Extracellular HSP27 Levels are Athero-protective in HSP27 o/e ApoE -/- Mice 6 HSP27 serum levels (pg/ml) pre-diet 4-wks 12-wks pre-diet 4-wks 12-wks HFD HFD HFD HFD Female Male Rayner et al., Circ Res 28 Cuerrier CM et al., PLoS ONE 213
8 Serum HSP27 Levels Are Lower in Patients With CAD T. Seibert et al. J Am Coll Cardiol. 213;62(16):
9 Serum HSP27 Levels Are Predictive of Future Cardiovascular Events T. Seibert et al. J Am Coll Cardiol. 213;62(16):
10 rhsp27 Anti-Atherosclerosis Rx rhsp27 Inactive truncated mutant C1 - Mice: ApoE -/- Females 4-wk 7-wk 1-wk Age Chow Diet High Fat Diet (HFD) Control: b.i.d., s.c. rhsp27: 1ug b.i.d., s.c. Sacrifice T. Seibert et al. J Am Coll Cardiol. 213;62(16):
11 rhsp27 Anti-Atherosclerosis Rx Aortic Lipid Content (Oil Red O) Aortic Root Atherosclerotic Burden T. Seibert et al. J Am Coll Cardiol. 213;62(16):
12 rhsp27 Rx Lowers Serum Cholesterol T. Seibert et al. J Am Coll Cardiol. 213;62(16):
13 Prolonged HSP27 Over-expression: Sustained Reduction in Cholesterol Levels T. Seibert et al. J Am Coll Cardiol. 213;62(16):
14 HSP27 Signals to Reduce Atherogenesis & Lipids Exosomal HSP27: - garbage trucks - mirna, cholesterol Altered Transcription: - SR-A: ê - GM-CSF: é - IL-1: ê - ABCA1 & ABCG1: é Modified from Cuerrier CM et al. PLoS ONE 213; 8(2): e55867.
15 Hypothesis HSP27 augments hepatic cholesterol uptake by reducing the expression of PCSK9, thereby increasing the availability of hepatic LDL-R.
16 Proprotein Convertase Subtilisin / Kexin type 9 (PCSK9) Statins
17 rhsp27 Lowers Extracellular ApoB-1 In vitro: HepG2 (Liver) Cells rhsp 27 rhsp 27 ApoB 1 ApoB-1 (AU / mg of total protein) P=.6 45% ApoB 1 (ng/ml) P=.2 24% ApoB-1 β-actin ApoB-1 (% vs β-actin) 8 P= Western blot of Secreted Proteins ELISA of Secreted Proteins Western blot of Intracellular Proteins rhsp27
18 rhsp27 Rx Promotes Intracellular TG and FC Retention rhsp 27 rhsp 27 CE TG FC CE TG FC Culture medium Cell extracts PC PC Culture medium TG (AU / mg of total protein) P=.1 Intracellular TG (AU / mg of total protein) P=.2 rhsp27
19 rhsp 27 Reduces PCSK9, Increases LDL-R & LDL Uptake rhsp27 rhsp27 PCSK9 LDLR β-actin β-actin 1 1 P=.1 PCSK9 protein level (%vs β-actin) P=.19 54% LDLR protein level (% vs β-actin) % rhsp27 Relative fluorescence (%) P=.22 28% rhsp27
20 rhsp27 Rx reduces Plasma & Liver PCSK9 In vivo: ApoE -/- Mice Rx rhsp27 PCSK9 Plasma PCSK9 (ng/ml) P=.1 57% PCSK9 protein level (% vs β-actin) β-actin P=.23 23% Liver PCSK9 (ng/mg) P=.3 16% Plasma Hepatocytes (Western Blot) Hepatocytes (ELISA) rhsp27
21 rhsp27 Rx Increases LDL-R Reduces Serum Cholesterol & Atherogenesis LDL-R protein level (% vs β-actin) LDLR β-actin % P=.3 ApoE -/- Mice Hepatocytes (Western Blot) Total Plasma cholesterol (mg/dl) P=.2 2% ApoE-/- cholesterol rhsp27 ApoE -/- mice fed high fat diet rhsp27
22 rhsp27 Rx Promotes Hepatic Cholesterol Uptake No Effect on HMG-CoA Reductase & SREBP-2 HMG-CoA R SREBP-2 rhsp27 β-actin β-actin Oil Red O Stain rhsp27 CE TG FFA FC HMG-CoA R protein level (% vs β-actin) P=.72 SREBP-2 protein level (% vs β-actin) P=.64 PC rhsp27
23 Study Limitations 1. In vivo pharmaco-kinetics of HSP27 Rx are evolving (optimization of dosing schedule & adjuvant therapy) 2. Significant reductions in PCSK9 & increase in LDL-R were achieved, yet only a 2% lowering of total plasma cholesterol 3. In vivo experiments involve only female mice and are being expanded to males and other (larger) animal models
24 Quantification of PCSK9 Mass Mass Spectrometry SILAC (Stable Isotope Labeling using Amino Acids in Cell Culture) HepG2 Liver Cells treated with rhsp27
25 Summary 1. HSP27 serum levels are athero-protective 2. HSP27 reduces PCSK9 & increases LDL-R expression 3. HSP27 reduces plasma cholesterol levels without altering HMG Co-A reductase or SREBP-2
26 Future Implications 1. Mechanism by which HSP27 reduces PCSK9? 2. Role of Anti-HSP27 Auto-antibodies? 3. HSP27 therapeutic strategies for hypercholesterolemia & atherosclerosis? 4. HSP27 acts as a downstream foot-soldier of estrogen: >>> mechanism of post-menopausal increase in PCSK9?
27 Research Team CUMMING SCHOOL OF MEDICINE O Brien Lab Ø Yong-Xiang Chen MD, PhD Ø Chunhua (Scott) Shi, PhD Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Zarah Batulan, PhD Yumei (Tony) Li, (PhD) Nadia Maarouf, (PhD) Daiana Alvarez-Olmeda (PhD) Li Zhang, PhD Michael Chiu, MD Yuan (Peter) Zhang (MD) Geremy Koumbadinga, PhD Ayinuer Adijiang, PhD Vivek Krishan, PhD Ø Jean-Claude Bakala N Goma, PhD Collaborations: Ø Jackie de Belleroche (Imperial College London) Ø Bill Gerthoffer (Univ S. Alabama) Ø Jonathan Dean (Kennedy Institute Rheumatology, Oxford) Ø Gillian Einstein (U of Toronto)
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