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2007-10-11 추계순환기학회 Hypertension 심포지움 Aldosterone and

1 추계순환기학회 Hypertension 심포지움 Aldosterone and NAD(P)H Oxidase in Hypertensive Vascular Remodeling 관동의대제일병원내과박정배

2 Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: a link?

3 A Model of the Systematic Circulation. Mean BP = CO Diastolic x TPR Systolic BP = CO x stiffness

Arterial changes in Hypertension Normotension Hypertension Hemodynamic: pressure, flow, cyclic stress Structure large small Hypertrophic Eutrophic remodeling Endothelium Endothelial

4 Arterial changes in Hypertension Normotension Hypertension Hemodynamic: pressure, flow, cyclic stress Structure large small Hypertrophic Eutrophic remodeling Endothelium Endothelial dysfunction Extra/intracellular stimuli: Ang II, ET-1, NO -, O ECM deposition Elastin Collagen x Altered vascular mechanics Park JB & Schiffrin EL. Curr Hypertens Reports 2000

5 Large and small artery - elastin - collagen Peak Eeff (effective Young s modulus) : collagen; ~10 8, elastin; 3x10 5, smooth muscle; ~ ? N/m 2

6 Resistance Artery Study in Human Gluteal subcutaneous biopsy Small artery studies (isobaric) Subcutaneous fat 60mmHg Park JB dissection Peripheral resistance artery (150 ~350 µm) Structure; media to lumen ratio Function; ach and nitroprusside Mechanics -intraluminal pressure = mmhg -lumen and media measurements

7 Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. Resistance Artery Vascular Remodeling - Media/Lumen ratio Hypertension Prevalence (%) Endothelial Function - Ach response Vascular Stiffness - E inc vs stress LV Mass ECG/ECHO No change Park JB, Schiffrin EL. J Hypertens 2001;19:921

8 Event-free survival in a group of patients with essential hypertension or diabetes mellitus and with a media lumen (M/L) ratio of subcutaneous small arteries and Incidence of cardiovascular events Rizzoni et al. Circulation 2003;108:2230 Rate of CV events x 100 patients/year ** M/L<0.11 M/L 0.11

9 1-Year Treatment Effects of Losartan and Atenolol on Small Artery Structure and Function in Hypertension Structure Endothelium-dependent relaxation Media/Lumen ratio (%) * Losartan before Losartan 1 year Atenolol before Atenolol 1 year * Maximal Acetylcholine Response (%) Schiffrin and Park..Circulation 2000

10 Arteriosclerosis & atherosclerosis of large artery Compliant Arterio and Atherosclerosis Systole Diastole Systole Diastole Constant Stroke Volume Aorta compliant stiffened Pulse pressure

11 Summary of Large and Small Artery Alterations in Hypertension Large Artery Remodeling Pulse wave velocity Arterial augmentation Characteristics impedance SV Vascular stiffness SBP Small Artery Remodeling Eutrophic remodeling Endothelial dysfunction Unaltered stiffness, initially stiffened, later Resistance to flow = 8 η L π r 4 DBP PVR Neurohormone Park JB. 2007

12 Arterial Dysfunction and CVD Endothelial dysfunction NO activity ROS CV risk factors DM, HT, etc Arterial Stiffness (arteriosclerosis) Cushioning function Atherosclerosis Conduit function Small artery remodeling SBP PP DBP Prevention and Interventions to Reduce Vascular Stiffening and Improve Arterial Function LVH Myocardial O2 demand Coronary perfusion CAD, CHF Death

13 Difference of CVD prediction between systolic and diastolic BP as a function of age 1.0 SBP SV & Art. stiffness Large a β(sbp)-β(dbp) DBP PVR & Neurohormone Small a β(sbp)-β(dbp) Age (year) Age (year) 2003 JNC VII Park JB 2006

14 Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: : a link?

15 Myocardial fibrosis experimental model (Aldosterone-salt Hypertension) HBP LVH Fibrosis Artery Ang II Aldo hypertrophic x Aldo + salt Ang II Aldo Ang II Aldo hypertrophic eutrophic Modified from Weber K group.

16 Systolic blood pressure, mmhg Aldo *** *** *** Aldo+BMS Control Media to lumen, % ** + Control Aldo Aldo+BMS Experiment period, week Hypertension 2001

17 Arterial Remodeling of Resistance Arteries in Hypertension Hypertrophic remodeling Experimental Hypertension Human Hypertension ETdominant M/L CSA DOCA salt 1-k 1c Dahl SS Renovascular HT Pheochromocytoma Normal Aldosterone RASdominant M/L CSA = SHR 2-k 1c Mild ~ moderate HT Eutrophic remodeling Intengan H and Schiffrin EL Hypertension (Modified )

18 Cardiac and Vascular Fibrosis and Hypertrophy in Aldosterone-Infused Rats: Role of Endothelin-1 Jeong Bae Park and Ernesto L. Schiffrin Control Aldo Aldo+BMS LV perivascular collagen Heart RV perivascular collagen Aorta intima-media collagen Collagen content, % ** ++ control aldo aldo+bms 3 * control aldo aldo+bms Control Aldo Aldo+BMS * BMS (BMS ) ETA-selective endothelin antagonist Am J Hypertens 2002

19 SUMMRY: NAD(P)H oxidase and cardiac fibrosis in aldosterone-salt rats SBP Cardiac hypertrophy P22 phox mrna NAD(P)H oxidase activity Aldosterone NAD(P)H oxidase inhibition Procollagen I and III TGF-β1 Fibrosis and perivascular and 2004 Park JB

20 Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-κ κb Activation in Ang II Induced Cardiac Injury Fiebeler A.. Müller DN. Park J-K et al. Hypertension2001;37:787

21 Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: a link?

22 ROS and Vascular alterations (the courtesy from Rhian M Touyz, 2004)

23 Aldosterone-Induced Inflammation in the Rat Heart Role of Oxidative Stress NADPH Oxidase Expression gp91phox 3-Nitrotyrosine Staining Activated NF-κB ED-1-positive macrophages Proinflammatory and profibrogenic cardiac phenotype intramural arteries heart in chronic ALDOST rats is related to an induction of oxidative and nitrosative stress and is prevented by antioxidant cotreatment. BrdU-positive cells Negative control Sun Y et al. Am J Pathol 2002

24 - BBRC 2004

25 Effect of aldosterone on NA(D)PH oxidase activity in aldosterone-induced fibrosis Iglarz M et al AJH

26 Association of aldosterone with NAD(P)H oxidase subunits (p47 phox )? gp91 Rap1A NAD(P)H rac Nox1 Nox4 Nox5 p67 p22 p47 p40 NAD(P) + + H +

27 Possible Pathway of Aldosterone on CV remodeling Ang II AT 1 Aldosterone?? NADH/NADPH oxidase? o 2 -> - o 2 ->H 2 O 2 Park JB Hypertension Endothelin nuclear signaling Protein synthesis Cell growth ECM deposition growth factor production CARDIO- VASCULAR REMODELING Park JB. 2003

28 Figure 4. Treatment with spironolactone attenuated NAD(P)H oxidase mrna expression in aorta(a) and kidney(b) of aldosterone-infused rats. The mrna expression of the NAD(P)H oxidase subunits p47phox, gp91phox and p22phox was markedly increased in aldosterone-infused rats. The treatment with spironolactone significantly reduced NAD(P)H oxidase subunits mrna expression. Losartan and apocynin decreased on NAD(P)H oxidase subunits mrna expression in aorta and kidney from aldosteroneinfused rats. *P< 0.05 vs. control rats; P<0.05, vs. aldosterone-infused rats.

29 Role of p47phox in vascular oxidative stress and hypertension caused by ang II In situ dihydroethidium staining Ang II Ang II+p47 -/- Sham Sham +p47 -/- Landmeser U Harrison D. Hypertension. 2002;40:511-5.

30 Role of a p47phox-containing NADPH oxidase in aldosterone-induced vascular oxidative stress and hypertrophy in mice Systolic Blood Pressure (mmhg) * * WT + Aldo p47 phox-/- p47 phox-/- + Aldo p47 phox-/- + Aldo + Spiro p47 phox-/- + Aldo + Apocynin *, p<0.001, WT+Aldo vs others Weeks 2007 unpublished, Park YM and Park JB

31 Relationship between aldosterone, and oxidative stress, inflammation, fibrosis

32 Aldosterone blockade and AT 1 R blockade: Trials in post-mi LV dysfunction and HF RALES EPHESUS Probability 0.75 of survival % Risk reduction RR 0.70 ( ) P < Spironolactone 25 mg Placebo Cumulative14 incidence 10 (%) % Risk reduction RR 0.85 ( ) P = Eplerenone 50 mg Placebo 36 Months Months Pitt B et al. N Eng J Med. 1999;341: Pitt B et al. N Eng J Med. 2003;348:

33 RAS blockade : where? Angiotensinogen DRI Vasodilation Prostaglandin β-b Renin Ang I BRADYKININ tpa Feedback Loop AA Aldosterone β-b; 베타차단제 DRI; 직접레닌억제제 ACEI; 안지오텐신전환효소억제제 ARB; 안지오텐신수용체 (AT 1 ) 차단제 AA; aldosterone antagonist Non-ACE Ang II ARB ACEI ACE ACEI Fragments AT 2 수용체 AT 1 수용체혈관이완알도스테론분비심혈관비대억제혈관수축항세포비대심혈관비대산화질소분비세포증식과비대소디움신장배설등교감신경항진등 2007 Park JB

34 Aldosterone, NAD(P)H oxidase and Vascular damage and Potential intervention ALDO ET-1 Ang II Ca ++ overload NAD(P)H oxidase Oxidative stress ROS RNS NK-κB Proinflammatory pathway Adhesion Inflammation Cytokine... Receptor CCB Antagonist NAD(P)H oxidase inhibitor antioxidant? PPARs Statin 2005 Park JB

35 CheongGyeCheon in Seoul 감사합니다. Thank you!

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$(Microsoft PowerPoint - S13-3_\261\350\273\363\307\366 [\310\243\310\257 \270\360\265\345])$ Cardiovascular Disease in Metabolic Syndrome 김상현 보라매병원내과 서울대학교의과대학내과학교실 Contents Metabolic syndrome and Cardiovascular system CVD Mortality Coronary artery disease Heart failure Atrial fibrillation Management