NAM JUNE PAIK: Rhapsody in Video

Size: px

Start display at page:

Download "NAM JUNE PAIK: Rhapsody in Video"

Britney Nichols
5 years ago
Views:

1 NAM JUNE PAIK: Rhapsody in Video

2 혈관연구회추계학회 Renin-angiotensin-aldosterone System Kwang Kon Koh, MD, FACC, FAHA Cardiology Gachon University Gil Medical Center Incheon, Korea

3 Cytokines oxldl Ang II LPS CMV NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria 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) Activation of Nuclear Transcription Factor, NF-κB AT 1 R Proinflammatory cytokines FFA IKKβ Oxygen Free Radicals p50 p65 p65 p50 IκB MCP-1 M-CSF E-Selectin CRP VCAM-1 Tissue factor ICAM-1 PAI-1 IκB P NF-κB Nucleus

4 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

5 Cross-talk Between RAS and Statin

6 Upregulation of AT1R mrna by ox-ldl, HCAECs AT1R density in HC Men Regression analysis Li et al, Circulation 2000;102:1970 Nickenig et al, Circulation 1999;100:2131

7 Effect of ox-ldl and Ang II on endothelial cell injury measured as LDH release Li et al, Circulation 2000;102:1970

8 Ang II-Induced Hypertension Accelerates Atherosclerosis in ApoE-Deficient Mice En face dissections of descending thoracoabdominal aorta after 8 weeks of treatment Weiss et al, Circulation 2001;103:448

9 Effect of Statin on tail-cuff Pr in Ang II HT in rats Statin-Sensitive Dysregulated AT1R Function in HC Men HC NC HC NC HC HC+S Delbosc et al, Hypertension 2002;40:142 Nickenig et al, Circulation 1999;100:2131

10 Simvastatin prevents Ang II-induced Oxidative stress and cardiac hypertrophy Delbosc et al, Hypertension 2002;40:142

11 Fluvastatin Enhances the Inhibitory Effects of a Selective AT 1 Receptor Blocker, Valsartan, on Atherosclerosis ApoE null (ApoEKO) Mice, 10 weeks Independent of BP or Cholesterol Levels A B E C F D G H Li Z et al, Hypertension. 2004;44:758.

12 Cytokines oxldl Ang II LPS CMV Activation of Nuclear Transcription Factor, NF-κB AT 1 R Ramipril, Losartan Statins MCP-1 M-CSF E-Selectin CRP VCAM-1 Tissue factor ICAM-1 PAI-1 NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria Statins LDL, NO Antioxidant HDL Oxygen Free Radicals 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) p50 p65 p65 p50 IκB IκB P NF-κB Nucleus

13 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

14 Effects of Simvastatin, Combined Therapy, and Ramipril on Flow-mediated Dilation 0 Malondialdehyde 100 FMD % Change in MDA Levels (%) P<0.05 P<0.05 Simvastatin Combined Therapy P<0.001 by ANOVA Ramipril % Change in Flow-Mediated Dilation (%) P<0.001 P=0.027 P<0.001 Simvastatin Combined Therapy P<0.001 by ANOVA Ramipril Koh KK, et al. Hypertension 2005;45:1088

15 ARBs: PPARγ Activity Pio ARBs Promote 3T3-L1 Adipocyte Differentiation Tel Irb Los ap2: adipogenic marker gene, adipose protein 2 Schupp M, et al. Circulation 2004;107:2054

16 Cross-talk between inflammatory and insulin signaling pathways causes both endo. dysfunction and metabolic insulin resistance that synergize to cardiovascular disorders in Met Syndrome Healthy INFLAMMATION Metabolic and Cardiovascular Diseases Endothelium IR Adipose Tissue Skeletal Muscle IR Endothelium IR Cytokines FFA Adipose Tissue Skeletal Muscle IR IRS-1 IRS-1 IRS-1 IKKβ IKKβ IRS-1 PI 3-Kinase PI 3-Kinase PI 3-Kinase PI 3-Kinase PDK-1 PDK-1 PDK-1 PDK-1 Akt Akt/PKCζ Akt Akt/PKCζ enos NO Vasodilation GLUT4 Translocation enos NO GLUT4 Translocation Endothelial Insulin Glucose Uptake Dysfunction Resistance Kim J, Koh KK, Quon MJ. Arterioscler Thromb Vasc Biol 2005;25:889.

17 Effects of Simvastatin, Combined Therapy, % Change in Adiponectin Levels (%) and Ramipril on Insulin Sensitivity Adiponectin P<0.05 P<0.05 P=0.013 by ANOVA % Change in QUICKI (%) QUICKI P<0.05 P<0.05 P=0.015 by ANOVA -10 Simvastatin Combined Therapy Ramipril -5 Simvastatin Combined Therapy Ramipril *QUICKI=Quantitative Insulin-Sensitivity Check Index, a surrogate index of insulin sensitivity, QUICKI = 1/[log(insulin)+log(glucose)]

18 Cross-talk Between RAS and PPAR

19 Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia 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

20 Downregulation of PPAR-α and PPAR-γ mrna In Aortas of apoe-ko Mice Treated with ANGII PPAR-α and PPAR-γ mrna In aortas of apo E-KO mice Histo- and IH appearance of suprarenal aorta THAM DM, et al. Physiol Genomics 2002;11:21

21 PPARα Activator Effects on Ang II-Induced Vascular Oxidative Stress and Inflammation Systolic BP in Ang II-infused rats treated with or without DHA (PPARα activator, docosahexaenoic acid) Diep et al, Hypertension 2002;40:866

22 Representative immunohistochemical Staining for ICAM in aorta of Ang II-infused rats with or without DHA Diep et al, Hypertension 2002;40:866

23 Transcriptional Suppression of AT 1 R Gene Expression by PPAR-γ Ligands in VSMCs AT 1 R mrna expression AT 1 R protein expression Sugawara A, et al. Endocrinology 2001;142:3125

24 Cytokines oxldl Ang II LPS CMV Activation of Nuclear Transcription Factor, NFκB Candesartan Fenofibrate MCP-1 M-CSF E Selectin ICAM-1 VCAM-1 Tissue PAI-1 factor NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria Oxygen Free Radicals p50 p65 p65 p50 IκB IκB P Fenofibrate HDL, NO Antioxidant TG, LDL Koh KK, JACC 2005;46:1978 (Review) Hypertension 2005;46:1086 (Review), Circulation 2006;113:1888 (Review)

25 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

26 Change in BP at Baseline and after Therapy In Hypertriglyceridemic, Hypertensive Patients Systolic Blood Pressure (mmhg) P<0.01 P<0.001 P<0.001 Baseline After therapy P<0.001 by ANOVA Diastolic Blood Pressure (mmhg) P<0.05 P<0.001 P< Fenofibrate Combined Therapy Candesartan 0 Fenofibrate Combined Candesartan Therapy Koh KK, et al. Diabetes Care 2006;29:195

27 % Change in MDA Levels (%) Combined Therapy Significantly Improves Flow-mediated Dilator Response Malondialdehyde P<0.05 P<0.05 P=0.002 by ANOVA Fenofibrate Combined Therapy Candesartan % Change in Flow-Mediated Dilation (%) FMD P<0.05 P<0.05 Fenofibrate Combined Therapy P<0.001 by ANOVA Candesartan Koh KK, et al. Diabetes Care 2006;29:195

28 Change in Insulin Sensitivity at Baseline and 5 after Therapy in HyperTG, HT Patients Baseline After therapy P=0.246 by ANOVA 0.6 P=0.153 by ANOVA Plasma Adiponectin Levels (µg/ml) P=0.153 P<0.001 P<0.001 QUICKI P=0.037 P=0.007 P= Fenofibrate Combined Therapy Candesartan 0.0 Fenofibrate Combined Therapy Candesartan Koh KK, et al. Diabetes Care 2006;29:195

29 Shared and Interacting Mechanisms Underlie Reciprocal Relationships Between IR and ED Glucotoxicity Lipotoxicity Inflammation Oxidative stress AGE formation Hexosamine Pathway Pro-inflammatory signaling Oxidative stress Pro-inflammatory signaling Ceramide Pro-inflammatory factors (TNF-α, IL-1β, IL-6, CRP) Kinases/transcription factors (JNK, IKKβ, NF-κB, AP-1) Insulin resistance Endothelial dysfunction Diabetes Obesity Dyslipidemia Coronary Artery Disease Hypertension Atherosclerosis Han SH, Quon MJ, Koh KK. Cur Op Lipidology 2007;18:58 (review)

30 Combination Activation Therapy of for Nuclear the Treatment of Atherosclerosis: Transcription Novel Factor, Emerging NFκBConcepts Cytokines oxldl Ang II LPS CMV NADH / NADPH oxidase Cyclooxygenase Lipoxygenase Xanthine oxidase Mitochondria Fibrates Statins AT 1 R Ramipril, ARBs Fenofibrate Statins HDL, NO Antioxidant TG, LDL Oxygen Free Radicals MCP-1 M-CSF E Selectin ICAM-1 VCAM-1 Tissue PAI-1 factor 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 p50 p65 p65 p50 IκB IκB P NF-κB Nucleus

33 Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Endo. Function Epicardial arterial vasorelaxation response to Bradykinin and calcium ionophore in pigs HC +HT HC+HT HT HC N HC HT Rodriguez-Porcel et al, Arterioscler Thromb Vasc Biol. 2003;23:885.

34 Adiponectin, cytokines secreted by adipose cells, Have insulin-sensitizing, anti-inflammatory, And anti-atherogenic properties Adiponectin Adiponectin Receptor AMPK enos reductase PI 3-kinase-dependent Pathways p reductase oxydase L-Arginine oxydase L-Citruline NO p65 p50 IκB NFκB IκB P p50 p65 Koh KK, et al. JACC 2005;46:1978, 2007;49:531, Cur Op Lipidology 2007;18:58 (review)

Novel Markers of Arterial Dysfunction

혈관연구회창립심포지움, 3 월 3 일, 2005 Novel Markers of Arterial Dysfunction Kwang Kon Koh, MD, FACC, FAHA Cardiology Gachon Medical School Incheon, Korea Atherosclerosis: A progressive process PHASE I: Initiation