Alan T. Remaley, MD, PhD Lipoprotein Metabolism Section Cardiovascular and Pulmonary Branch National Heart, Lung and Blood Institute National Institutes of Health Conflicts of Interests: Research grants with MedImmune, Shire, Corvidia, and Liposcience Cardiovascular Disease and Inflammation: What Can HDL Do About It?
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Alan T. Remaley, MD, PhD
Lipoprotein Metabolism SectionCardiovascular and Pulmonary Branch
National Heart, Lung and Blood InstituteNational Institutes of Health
Conflicts of Interests: Research grants with MedImmune, Shire, Corvidia, and Liposcience
Cardiovascular Disease and Inflammation: What Can HDL
Do About It?
Overview
• History of Cholesterol Research
• Lipoprotein Metabolism
• Pathogenesis of Atherosclerosis
• HDL and Inflammation
History of Cardiovascular Disease Research
Rudolf Virchow 1821-1902
H. Anitchkov1885-1964
Cholesterol
(factor in CHD)
LDL
(Bad - chol)
HDL
(neutral)
LDL
(Bad - chol)
HDL
(Good - chol)
Ox-LDL
(Very Bad - chol)
LDL
subfractions
Non-HDL
Lipoproteins
Dysfunctional
HDL
Bad HDL
Good HDL
1905 1920’s-1950’s 1970’s 1980’s 1990’s 2000’s
Evolution of Cholesterol as a CHDRisk Biomarker
Cholesterol
(factor in CHD)
LDL
(Bad - chol)
HDL
(neutral)
LDL
(Bad - chol)
HDL
(Good - chol)
Ox-LDL
(Very Bad - chol)
LDL
subfractions
Non-HDL
Lipoproteins
Dysfunctional
HDL
Bad HDL
Good HDL
1905 1920’s-1950’s 1970’s 1980’s 1990’s 2000’s
Evolution of Cholesterol as a CHDRisk Biomarker
Cholesterol
(factor in CHD)
LDL
(Bad - chol)
HDL
(neutral)
LDL
(Bad - chol)
HDL
(Good - chol)
Ox-LDL
(Very Bad - chol)
LDL
subfractions
Non-HDL
Lipoproteins
Dysfunctional
HDL
Bad HDL
Good HDL
1905 1920’s-1950’s 1970’s 1980’s 1990’s 2000’s
Evolution of Cholesterol as a CHDRisk Biomarker
Cholesterol
(factor in CHD)
LDL
(Bad - chol)
HDL
(neutral)
LDL
(Bad - chol)
HDL
(Good - chol)
Ox-LDL
(Very Bad - chol)
LDL
subfractions
Non-HDL
Lipoproteins
Dysfunctional
HDL
Bad HDL
Good HDL
1905 1920’s-1950’s 1970’s 1980’s 1990’s 2000’s
Evolution of Cholesterol as a CHDRisk Biomarker
Early Lipoprotein Research at the NIH
Circa mid 1960s
Overview
• History of Cholesterol Research
• Lipoprotein Metabolism
• Pathogenesis of Atherosclerosis
• HDL and Inflammation
Chylomicron
VLDL
IDL
LDL
HDL
Lp(a)
CholesterolProteinTriglyceridePhospholipid
Major Classes of Lipoproteins
Lipoprotein Metabolism Pathways
Lipoprotein Metabolism Pathways
Triglyceridedelivery
for energy metabolism
Lipoprotein Metabolism Pathways
Cholesterol Removal
HDL Structure and Composition
Pre-beta Discoidal Shaped HDL
Alpha Spherical Shaped HDL
Initial Cholesterol Acceptor Delivers Cholesterol to Liver
HDL transports over 80 different
proteins and over 200 species
of lipids.
Pleiotropic Anti-AtherogenicEffects of HDL
Antiinflammatory
Activity
Reverse
Cholesterol
Transport
Antithrombotic
Activity
Antiapoptotic
Activity
Antioxidative
Activity
Antiinfectious
Activity
Epithelial
Repair
Vasodilatory
Activity
Curr Med Res Opin 2004:20:1253-1268
Annu Rev Med 2003:53:321-341
Antiinflammatory
Activity
Reverse
Cholesterol
Transport
Antithrombotic
Activity
Antiapoptotic
Activity
Antioxidative
Activity
Antiinfectious
Activity
Epithelial
Repair
Vasodilatory
Activity
Curr Med Res Opin 2004:20:1253-1268
Annu Rev Med 2003:53:321-341
Pleiotropic Anti-AtherogenicEffects of HDL
Reverse Cholesterol Transport Pathway
Reverse Cholesterol Transport Pathway
Cholesterol Esterification
Reverse Cholesterol Transport Pathway
Reverse Cholesterol Transport Pathway
Reverse Cholesterol Transport Pathway
C
LIVER
LCAT
DiscoidalHDL
Diffusion
CellMembrane
TranslocationStep
SphericalHDL
Dissociation
KIDNEY
Free Apo A-I
HL
CETP
ABCAI“Flippase”
2 ATP 2 ADP
Apo A-IBinding Site
Apo A-IBinding Site
C
Association
Apo A-I
C
Secretion
C
C
CE
Model of Cholesterol Efflux to HDL
Overview
• History of Cholesterol Research
• Lipoprotein Metabolism
• Pathogenesis of Atherosclerosis
• HDL and Inflammation
M-CSFMCP-1
VCAM-1
Early Inflammatory Mediatorsof Atherosclerosis
LDL Uptake
Lumen
LipidCore
Fibrous cap
Shoulder
Intima
MediaElasticlaminæ
Internal
External
Calcification
Features of a Complex Atherosclerotic Plaque
No symptoms + Symptoms
Time (y)
Symptoms
Lesion initiation
Ischemic HeartDisease
CerebrovascularDisease
Peripheral VascularDisease
Schematic Timeline for Atherogenesis
Ruptured Atherosclerotic Plaque
Thrombus
Necrotic LipidCore Ruptured
FibrousCap
ThickenedMedia
100 160 220
HDL-C is an Independent CVD risk factor
HDL-C
(mg/dL)LDL-C (mg/dL)
25
Gordon T et al. Am J Med 1977;62:707-714.
4565
85
”Bad Cholesterol”
”Good Cholesterol”
Multiple Anti-atherogenic Effects of HDL
HDL
LDL
LDL
Ox
LDL
Inhibition of
LDL-oxidation
Inhibition of
monocyte-
adhesion
Cholesterol-
efflux
HDL
HDL
HDL
Endothelium
mono-
cyte
macro-
phagefoam
cell
Inhibition of
LDL Infiltration
Modulation of LDL-C versus HDL-C for CHD Risk Reduction
Modulation of LDL-C versus HDL-C for CHD Risk Reduction
First Major Crack in HDL Hypothesis
Torcetrapib
Illuminate Phase 3 trialhalted for increased CVD events
Forbes, April 2007 Bartrer P et al. NEJM 2007
HDL-C: 72% increaseLDL-C: 25% decrease
Overview
• History of Cholesterol Research
• Lipoprotein Metabolism
• Pathogenesis of Atherosclerosis
• HDL and Inflammation
Potential Anti-inflammatory Mechanisms of HDL
• Cholesterol Removal-Both cellular and extracellular
• Sequestration of oxidized lipids/LPS/cytokines
• Delivery of Anti-inflammatory Proteins and Lipid Cargo
Potential Anti-inflammatory Mechanisms of HDL
• Cholesterol Removal-Both cellular and extracellular
• Sequestration of oxidized lipids/LPS/cytokines
• Delivery of Anti-inflammatory Proteins and Lipid Cargo