Download - NAM JUNE PAIK: Rhapsody in Video
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NAM JUNE PAIK: Rhapsody in Video
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Kwang Kon Koh, MD, FACC, FAHA
Cardiology
Gachon University Gil Medical Center
Incheon, Korea
Renin-angiotensin-aldosterone
System
혈관연구회혈관연구회혈관연구회혈관연구회 추계학회추계학회추계학회추계학회 2007.10.13
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MCP-1 M-CSF
E-Selectin CRP
VCAM-1 Tissue factor
ICAM-1 PAI-1
NADH / NADPH oxidaseCyclooxygenase
Lipoxygenase
Xanthine oxidase
Mitochondria
Oxygen Free
Radicals
p65p50
p65p50
IκκκκB
Cytokines
oxLDL
Ang IILPS
CMV
PIκκκκB
Activation of Nuclear
Transcription Factor, NF-κκκκB
Koh KK. JACC 2005;46:1978
Hypertension 2005;46:1086
Circulation 2006;113:1888
JACC 2007;49:531
Curr Op Lipidol 2007;18:58
Hypertension 2007 (in press)
NF-κB
Nucleus
Proinflammatory
cytokines
FFA
IKKββββ
AT1R
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Combination Therapy for The Treatment of Atherosclerosis:
Evidence from Novel Emerging Concepts
� Nov 8: Methodist Hospital,
Baylor College of Medicine, Houston
� Dec 6: Cardiology Grand Rounds,
Brigham and Women’s Hospital,
Harvard Medical School, Boston
� April 1: ACC 2008 Meeting, Chicago
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Cross-talk Between
RAS and Statin
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Upregulation of
AT1R mRNA
by ox-LDL, HCAECs
Li et al, Circulation 2000;102:1970
AT1R density in HC Men
Regression analysis
Nickenig et al, Circulation 1999;100:2131
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Effect of ox-LDL and Ang II on endothelial
cell injury measured as LDH release
Li et al, Circulation 2000;102:1970
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Ang II-Induced Hypertension Accelerates
Atherosclerosis in ApoE-Deficient MiceEn face dissections of descending thoraco-
abdominal aorta after 8 weeks of treatment
Weiss et al, Circulation 2001;103:448
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Effect of Statin on
tail-cuff Pr in
Ang II HT in rats
Delbosc et al, Hypertension 2002;40:142
Statin-Sensitive Dysregulated
AT1R Function in HC Men
Nickenig et al, Circulation 1999;100:2131
HC
HC
HC
HC+S
NC
NC
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Simvastatin prevents Ang II-induced
Oxidative stress and cardiac hypertrophy
Delbosc et al, Hypertension 2002;40:142
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Fluvastatin Enhances the Inhibitory Effects of a Selective
AT1 Receptor Blocker, Valsartan, on Atherosclerosis
Li Z et al, Hypertension. 2004;44:758.
A B E C F D G HApoE null (ApoEKO) Mice, 10 weeks
Independent of BP or Cholesterol Levels
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Koh KK. JACC 2005;46:1978, Hypertension 2005;46:1086, Circulation 2006;113:1888,
JACC 2007;49:531, Curr Op Lipidol 2007;18:58, Hypertension 2007 (in press)
MCP-1 M-CSF
E-Selectin CRP
VCAM-1 Tissue factor
ICAM-1 PAI-1
NADH / NADPH oxidaseCyclooxygenase
Lipoxygenase
Xanthine oxidase
Mitochondria
Oxygen Free
Radicals
p65p50
p65p50
IκκκκB
Cytokines
oxLDL
Ang IILPS
CMV
PIκκκκB
↓↓↓↓ LDL, ↑↑↑↑ NO•Antioxidant↑↑↑↑ HDL
Activation of Nuclear
Transcription Factor, NF-κκκκB
Statins
Ramipril, Losartan
Statins
NF-κBNucleus
AT1R
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Beneficial Vascular and Metabolic Effects of Combined
Therapy with Ramipril and Simvastatin in 50 Patients with
Type 2 Diabetes
Kwang Kon Koh, Michael J. Quon*
Seung Hwan Han….. Eak Kyun Shin
Cardiology, Gachon Medical School, Korea
Diabetes Unit, NIH, USA*
Hypertension 2005;45:1088
Reuters Health 2005-06-16
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Effects of Simvastatin, Combined Therapy,
and Ramipril on Flow-mediated Dilation
% Change in Flow-Mediated Dilation (%)
0
20
40
60
80
100
Simvastatin CombinedTherapy
Ramipril
P<0.001 P<0.001
P<0.001by ANOVA
P=0.027
% Change in MDA Levels (%)
-40
-30
-20
-10
0
Simvastatin CombinedTherapy
Ramipril
P<0.05 P<0.05
P<0.001by ANOVA
Malondialdehyde FMD
Koh KK, et al. Hypertension 2005;45:1088
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ARBs Promote 3T3-L1
Adipocyte Differentiation
Schupp M, et al. Circulation 2004;107:2054
aP2: adipogenic marker gene, adipose protein 2
ARBs: PPARγγγγ Activity
Pio
Tel
Irb
Los
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Vasodilation
eNOS
Glucose Uptake
HealthyMetabolic and Cardiovascular
Diseases
IR
IRS-1
PI 3-Kinase
PDK-1
Akt
EndotheliumAdipose Tissue
Skeletal Muscle
Endothelial
Dysfunction
Adipose TissueSkeletal Muscle
FFA
IKKββββ IKKββββ
Cytokines
INFLAMMATION
NO
GLUT4
Translocation
IR
IRS-1
PI 3-Kinase
PDK-1
Akt/PKCζζζζ
eNOS
Insulin
Resistance
IR
IRS-1
PI 3-Kinase
PDK-1
Akt
Endothelium
NO
GLUT4
Translocation
IR
IRS-1
PI 3-Kinase
PDK-1
Akt/PKCζζζζ
Kim J, Koh KK, Quon MJ. Arterioscler Thromb Vasc Biol 2005;25:889.
Cross-talk between inflammatory and insulin signaling pathways
causes both endo. dysfunction and metabolic insulin resistance
that synergize to cardiovascular disorders in Met Syndrome
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Effects of Simvastatin, Combined Therapy,
and Ramipril on Insulin Sensitivity
% Change in Adiponectin Levels (%)
-10
0
10
20
30
Simvastatin CombinedTherapy
Ramipril
P<0.05
P<0.05
P=0.013by ANOVA
% Change in QUICKI (%)
-5
0
5
10
Simvastatin CombinedTherapy
Ramipril
P<0.05
P<0.05
P=0.015by ANOVA
*QUICKI=Quantitative Insulin-Sensitivity Check Index, a surrogate index
of insulin sensitivity, QUICKI = 1/[log(insulin)+log(glucose)]
Adiponectin QUICKI
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Cross-talk Between
RAS and PPAR
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Kwang Kon Koh, Michael J. Quon*
Seung Hwan Han….. Eak Kyun Shin
Cardiology, Gachon Medical School, Korea
Diabetes Unit, NIH, USA*
Diabetes Care 2005;28:1419
Beneficial Effects of Fenofibrate to
Improve Endothelial Dysfunction and
Raise Adiponectin Levels in Patients
With Primary Hypertriglyceridemia
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PPAR-αααα and PPAR-γγγγ mRNA In aortas of apo E-KO mice
THAM DM, et al. Physiol Genomics 2002;11:21
Histo- and IH appearance of
suprarenal aorta
Downregulation of PPAR-αααα and PPAR-γγγγ mRNAIn Aortas of apoE-KO Mice Treated with ANGII
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PPARαααα Activator Effects on Ang II-Induced Vascular Oxidative Stress and InflammationSystolic BP in Ang II-infused rats treated with or
without DHA (PPARα activator, docosahexaenoic acid)
Diep et al, Hypertension 2002;40:866
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Representative immunohistochemical
Staining for ICAM in aorta of
Ang II-infused rats with or without DHA
Diep et al, Hypertension 2002;40:866
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Transcriptional Suppression of AT1R Gene
Expression by PPAR-γγγγ Ligands in VSMCs
Sugawara A, et al. Endocrinology 2001;142:3125
AT1R mRNA
expression
AT1R protein
expression
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MCP-1 M-CSF
E Selectin ICAM-1
VCAM-1 Tissue
PAI-1 factor
NADH / NADPH oxidaseCyclooxygenase
Lipoxygenase
Xanthine oxidase
Mitochondria
Oxygen Free
Radicals
p65p50
p65p50
IκκκκB
Cytokines
oxLDL
Ang IILPS
CMV
PIκκκκB
↑↑↑↑ HDL, ↑↑↑↑ NO•Antioxidant
↓↓↓↓ TG, ↓↓↓↓ LDL
Activation of Nuclear
Transcription Factor, NFκκκκB
Feno-
fibrate
Candesartan
Fenofibrate
Koh KK, JACC 2005;46:1978 (Review)
Hypertension 2005;46:1086 (Review), Circulation 2006;113:1888 (Review)
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Additive Beneficial Effects of Fenofibrate
Combined with Candesartan
In Treatment of Hypertriglyceridemic,
Hypertensive Patients
Kwang Kon Koh, Michael J. Quon*
Seung Hwan Han….. Eak Kyun Shin
Cardiology, Gachon Medical School, Korea
Diabetes Unit, NIH, USA*
Diabetes Care 2006;29:195
Reuters Health 2006-02-27
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Systolic Blood Pressure (mmHg)
0
40
80
120
160 Baseline
After therapyP<0.01
Fenofibrate CombinedTherapy
Candesartan
P<0.001P<0.001
P<0.001by ANOVA
Change in BP at Baseline and after Therapy
In Hypertriglyceridemic, Hypertensive Patients
Diastolic Blood Pressure (mmHg)
0
40
80
120
P<0.05
Fenofibrate CombinedTherapy
Candesartan
P<0.001P<0.001
Koh KK, et al. Diabetes Care 2006;29:195
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% Change in Flow-Mediated Dilation (%)
0
20
40
60
80
100
Fenofibrate CombinedTherapy
Candesartan
P<0.05 P<0.05
P<0.001by ANOVA
% Change in MDA Levels (%)
-20
-10
0
10
Fenofibrate CombinedTherapy
Candesartan
P<0.05 P<0.05
P=0.002by ANOVA
Malondialdehyde FMD
Combined Therapy Significantly Improves
Flow-mediated Dilator Response
Koh KK, et al. Diabetes Care 2006;29:195
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Plasma Adiponectin Levels (µµ µµg/mL)
0
1
2
3
4
5
P=0.153
Fenofibrate CombinedTherapy
Candesartan
P<0.001P<0.001
Baseline
After therapy
Change in Insulin Sensitivity at Baseline and
after Therapy in HyperTG, HT Patients
QUICKI
0.0
0.2
0.4
0.6
P=0.037
Fenofibrate CombinedTherapy
Candesartan
P=0.021P=0.007
P=0.246 by ANOVA P=0.153 by ANOVA
Koh KK, et al. Diabetes Care 2006;29:195
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Glucotoxicity Lipotoxicity Inflammation
Insulin
resistance
Endothelial
dysfunction
•Oxidative stress
•AGE formation
•Hexosamine Pathway
•Pro-inflammatory signaling
•Oxidative stress
•Pro-inflammatory signaling
•Ceramide
•Pro-inflammatory factors
(TNF-αααα, IL-1ββββ, IL-6, CRP)•Kinases/transcription factors
(JNK, IKKββββ, NF-κκκκB, AP-1)
Diabetes
Obesity
Dyslipidemia
Coronary Artery Disease
Hypertension
Atherosclerosis
Shared and Interacting Mechanisms Underlie
Reciprocal Relationships Between IR and ED
Han SH, Quon MJ, Koh KK. Cur Op Lipidology 2007;18:58 (review)
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Koh KK. JACC 2005;46:1978, Hypertension 2005;46:1086, Circulation 2006;113:1888
JACC 2007;49:531, Curr Op Lipid 2007;18:58, Hypertension 2007, Endo Review 2007
MCP-1 M-CSF
E Selectin ICAM-1
VCAM-1 Tissue
PAI-1 factor
NADH / NADPH oxidaseCyclooxygenase
Lipoxygenase
Xanthine oxidase
Mitochondria
Oxygen Free
Radicals
p65p50
p65p50
IκκκκB
Cytokines
oxLDL
Ang IILPS
CMV
PIκκκκB
↑↑↑↑ HDL, ↑↑↑↑ NO•Antioxidant
↓↓↓↓ TG, ↓↓↓↓ LDL
Activation of Nuclear
Transcription Factor, NFκκκκB
Fibrates
Statins
Ramipril, ARBs
Fenofibrate
StatinsAT1R
NF-κBNucleus
Combination Therapy for the Treatment of
Atherosclerosis: Novel Emerging Concepts
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Hypercholesterolemia and Hypertension Have
Synergistic Deleterious Effects on Endo. Function
Rodriguez-Porcel et al, Arterioscler Thromb Vasc Biol. 2003;23:885.
Epicardial arterial vasorelaxation response to
Bradykinin and calcium ionophore in pigs
N
HCHT
HC
+HTHC+HT
HTHC
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NO
PI 3-kinase-dependent
Pathways
eNOS reductase
oxydase
Adiponectin
reductasep
oxydase
L-Arginine
L-Citruline
AMPK
Adiponectin
Receptor
p65p50
p65p50
IκB
PIκB
Adiponectin, cytokines secreted by adipose cells,
Have insulin-sensitizing, anti-inflammatory,
And anti-atherogenic properties
NFκκκκB
Koh KK, et al. JACC 2005;46:1978, 2007;49:531, Cur Op Lipidology 2007;18:58 (review)