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Ed O’ Brien, Jean-Claude Bakala-N’Goma, Chunhua Shi Cumming School of Medicine

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. Heat Shock Protein 27 (HSP27).

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Ed O’ Brien, Jean-Claude Bakala-N’Goma, Chunhua Shi Cumming School of Medicine

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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, anti-inflammatory, lipid lowering (serum / plaque), etc. • Signal from the “outside – in” via TLR4, etc. • Emerging role of anti-HSP27 auto-antibodies

  3. Serum HSP27 Levels Are Lower in Patients With CAD T. Seibert et al. J Am Coll Cardiol. 2013;62(16):1446-1454

  4. Serum HSP27 Levels Are Predictive of Future Cardiovascular Events T. Seibert et al. J Am Coll Cardiol. 2013;62(16):1446-1454

  5. Hypothesis HSP27 augments hepatic cholesterol uptake by reducing the expression of PCSK9 thereby increasing the availability of hepatic LDL-R.

  6. Proprotein Convertase Subtilisin / Kexin type 9 (PCSK9) Statins

  7. A rHSP27 PBS Heat Shock Protein 27 Reduces PCSK9 & Increases LDL Receptor Protein Levels in HepG2 Liver Cells rHSP27 PBS LDLR PCSK9 β-Actin β-Actin 54% P= 0.019 PCSK9 protein level (% vs β-Actin) LDLR protein level (% vs β-Actin) 67% P=0.001 PBS rHSP27

  8. Heat Shock Protein 27 Reduces Plasma PCSK9 Protein Levels & Increases LDL Receptor Levels in ApoE -/- mice 57% Plasma PCSK9 (ng/ml) rHSP27 PBS LDLR β-Actin 51% LDLR protein level (% vs β-Actin) rHSP27 PBS P= 0.001 P= 0.003

  9. Summary • HSP27 serum levels are athero-protective • HSP27 reduces PCSK9 & increases LDL-R expression • HSP27 reduces plasma cholesterol levels without altering HMG Co-A reductase or SREBP-2

  10. Future Implications • Mechanism by which HSP27 reduces PCSK9? • Role of Anti-HSP27 Auto-antibodies? • HSP27 therapeutic strategies for hypercholesterolemia & atherosclerosis? • HSP27 acts as a downstream “foot-soldier” of estrogen: >>> mechanism of post-menopausal increase in PCSK9?

  11. Research Team CUMMING SCHOOL OF MEDICINE O’Brien Lab • Yong-Xiang Chen MD, PhD • Chunhua (Scott) Shi, PhD • ZarahBatulan, PhD • Yumei(Tony) Li, (PhD) • Nadia Maarouf, (PhD) • Daiana Alvarez-Olmeda (PhD) • Li Zhang, PhD • Michael Chiu, MD • Yuan (Peter) Zhang (MD) • GeremyKoumbadinga, PhD • AyinuerAdijiang, PhD • VivekKrishan, PhD • Jean-Claude BakalaN’Goma, PhD • Collaborations: • Jackie de Belleroche (Imperial College London) • Bill Gerthoffer(Univ S. Alabama) • Jonathan Dean (Kennedy Institute Rheumatology, Oxford) • Gillian Einstein (U of Toronto) www.vascularnetwork.ca

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