novel reduction of pcsk9 expression: mechanistic insights into the anti-atherosclerotic &...
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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 [email protected]
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
T. Seibert et al. J Am Coll Cardiol. 2013;62(16):1446-1454
Serum HSP27 Levels Are Lower in Patients With CAD
Serum HSP27 Levels Are Predictive of Future Cardiovascular Events
T. Seibert et al. J Am Coll Cardiol. 2013;62(16):1446-1454
Hypothesis
HSP27 augments hepatic cholesterol uptake by
reducing the expression of PCSK9 thereby
increasing the availability of hepatic LDL-R.
Proprotein Convertase Subtilisin / Kexin type 9 (PCSK9)
Statins
PBSA
rHSP27
PCSK9
β-Actin
54%
PC
SK
9 p
rote
in l
evel
(%
vs
β-A
ctin
)
0
20
40
60
80
100
P= 0.019
PBS rHSP27
rHSP27
LDLR
PBS
β-Actin
LD
LR
pro
tein
lev
el
(% v
s β
-Act
in)
0
20
40
60
80
100P=0.001
67%
Heat Shock Protein 27 Reduces PCSK9 & Increases LDL Receptor Protein Levels in HepG2 Liver Cells
0
10
20
30
40
50
Pla
sma
PC
SK
9 (n
g/m
l)
57%
P= 0.001
PBSrH
SP27
LDLR
β-Actin
LD
LR
pro
tein
lev
el
(% v
s β
-Act
in)
0
20
40
60
80
100
51%
P= 0.003
PBS rHSP27
Heat Shock Protein 27 Reduces Plasma PCSK9 Protein Levels & Increases LDL Receptor Levels in ApoE -/- mice
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
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?
Research Team
O’Brien LabYong-Xiang Chen MD, PhD
Chunhua (Scott) Shi, PhDZarah Batulan, PhDYumei (Tony) Li, (PhD)Nadia Maarouf, (PhD)Daiana Alvarez-Olmeda (PhD)Li Zhang, PhDMichael Chiu, MDYuan (Peter) Zhang (MD)Geremy Koumbadinga, PhDAyinuer Adijiang, PhDVivek Krishan, PhD
Jean-Claude Bakala N’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)
CUMMING SCHOOL OF MEDICINE
www.vascularnetwork.ca