diet, vascular disease, and progenitor cellswcm/@global/documents/... · anthony rosenzweig, md...
TRANSCRIPT
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Anthony Rosenzweig, MD
Cardiovascular Institute
Beth Israel Deaconess Medical Center
AHA BCVS
July 22, 2010
Diet, Vascular Disease, and Progenitor Cells
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Diet and atherosclerosis in ApoE-/- mice
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Effects of a LCHP Diet in Mice
Weight Gain
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Atherosclerosis in mice is increased on LCHP Diet
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Effects of a LCHP Diet in Mice
Cholesterol oxLDL 8-oxoguanine
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Serum Concentration SC WD LCHP
Total cholesterol (mg/dL) 358.7 ± 28.3 1470 ± 170.7 1408 ± 251.2
High-density lipoprotein (mg/dL) 190.7 ± 6.1 861 ± 146.9 756 ± 121.1
Triglycerides (mg/dL) 108.0 ± 6.9 95 ± 27.8 155 ± 60.7
Glucose (fasting; mg/dL) 136 ± 6.9 185 ± 20.5 142 ± 17.7
Glucose (non-fasting; mg/dL) NA 406.9 ± 58.9 274.2 ± 51.0
Insulin (ng/ml) 307.5 ± 322.2 432.9 ± 477.9 308.5 ± 205.4
Effects of a LCHP Diet in Mice
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Inflammation is not increased on LCHP Diet
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Why is Atherogenesis Increased on LCHP diet?
Increased atherosclerosis not accounted for by:
• Serum lipids, insulin, or glucose
• Systemic or vascular inflammation
• Oxidative stress
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“The great tragedy of Science: the slaying of a
beautiful hypothesis by an ugly fact”
-- Thomas Henry Huxley
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Is there a counter-balance to vascular injury?
Vascular Progenitor Cell
Endothelial CellPericyte
InjuryRepair
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Vascular (Endothelial) Progenitor Cells
• Present in bone-marrow and peripheral blood
• Peripheral levels decrease with:
• Diabetes
• Smoking
• Hypercholesterolemia
• Coronary disease
• Peripheral levels increase with:
• Exercise
• Statin treatment
• Correlate with better vascular function
NEJM 2003
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0
20
40
60
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100
120
140
160
180
Nu
mb
er
of
CF
U-E
PC
at
6 w
ee
ks
SC WD LCHP SC WD LCHP
*#
ApoE +/+ApoE -/-
*#
Bone marrow EPCs are Decreased on LCHP diet
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SC WD LCHP
Sca1-F
ITC
Flk1-PE
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
% c
han
ge
vers
us
SC
co
ntr
ol
SC WD LCHP
Circulating EPCs are Decreased on LCHP Diet
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p-Akt is decreased by LCHP diets in EPCs
p-Akt in lin-, Flk-1+ cells
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Murine Hindlimb Ischemia Model
Niiyama H, Huang NF, Rollins MD, Cooke JP (2009).JoVE. 23. http://www.jove.com
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LCHP
WD
Neovascularization in a hindlimb ischemia model (WT)
0
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0.2
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0.8
0.9
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0 5 10 15 20 25 30
Days post-surgery
Flu
x isch
em
ic / n
on
-isch
em
ic lim
b
##
#
WD
LCHP
Ischemia-induced Neovascularization is Impaired on LCHP Diet
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Working Hypothesis: Balance Between Injury and Repair
Vascular Progenitor Cell
Pericyte
Injur
y
Repair
SC WD LCHP
Injury Repair
Endothelial Cell
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The Problem: What‟s a Vascular Progenitor Cell?
Vascular Progenitor Cell
PericyteEndothelial Cell
Humans:
• CD34
• CD133
• KDR (VEGFR)
• Mature markers absent
• Endothelial Colony formation
•Ac-LDL, Lectin binding
Mice:
• Sca-1
• Flk1
• Mature markers absent
• Endothelial Colony formationEndothelial Colony Matrigel Tube
Formation
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Phage Display for Novel VPC Markers
4 cycles of positive
selection
Positive Selection:
Lineage-negative, Flk-1-
positive BMCs
Negative selection:
Lineage-negative, Flk-1-
negative BMCs
6 „hits‟Ralph Weissleder
Kimberly Kelly
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0
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No
. o
f C
FU
s (
av
g p
er
1x10
6cells)
CFU-EPC assay +/- phage+ cells
Control + Phage
Control
P46
P46-positive Cells Enhance Endothelial Colony and Tube-Formation
Tube Formation in vitro
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In Vivo Staining of Endogenous Neovasculature with Phage
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Tie2-GFP CD31-Rhodamine DAPI
Ischemic
Limb
Control
Limb
Adoptive Transfer of P46-Positive Bone Marrow from
Tie2-GFP mice into Hind-Limb Ischemia Model
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Summary
• Dietary macronutrients (other than fat) can modulate
atherogenesis and neovascularization without altering
vascular inflammation in mice.
• These studies do not distinguish between the effects of low
carbohydrate and those of high protein in the diet.
• Vascular pathology may reflect a balance between injury
and repair.
• The role vascular progenitors warrants further evaluation in
animal models and people, but will likely require more
specific markers of
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Collaborators
Rosenzweig LabShi Yin Foo
Dorota Sadowicz
Matt Coggins
Saumya Das
BIDMC Cath Lab
Joanna Wyrkrykowska
Riya Chacko
Mike Rosenberg
MGH
Ralph Weissleder
Kimberly Kelly
Robert E. Gerszten
Eric Heller
Kathryn J. Moore
Jennifer J. Manning-Tobin
Center for Life Sciences
Cardiac
Diabetes
Network
National Heart
Lung and Blood Institute
People Science Health