nam june paik: rhapsody in video

NAM JUNE PAIK: Rhapsody in Video

Kwang Kon Koh, MD, FACC, FAHA

Cardiology

Gachon University Gil Medical Center

Incheon, Korea

Renin-angiotensin-aldosterone

System

혈관연구회혈관연구회혈관연구회혈관연구회 추계학회추계학회추계학회추계학회 2007.10.13

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

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

Cross-talk Between

RAS and Statin

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

Effect of ox-LDL and Ang II on endothelial

cell injury measured as LDH release

Li et al, Circulation 2000;102:1970

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

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

Simvastatin prevents Ang II-induced

Oxidative stress and cardiac hypertrophy

Delbosc et al, Hypertension 2002;40:142

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

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

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

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

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

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

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

Cross-talk Between

RAS and PPAR

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

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

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

Representative immunohistochemical

Staining for ICAM in aorta of

Ang II-infused rats with or without DHA

Diep et al, Hypertension 2002;40:866

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

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)

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

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

% 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

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

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)

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

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

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)