2007-10-11 추계순환기학회 Hypertension 심포지움 Aldosterone and NAD(P)H Oxidase in Hypertensive Vascular Remodeling 관동의대제일병원내과박정배
Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: a link?
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 dysfunction Extra/intracellular stimuli: Ang II, ET-1, NO -, O 2-... ECM deposition Elastin Collagen x Altered vascular mechanics Park JB & Schiffrin EL. Curr Hypertens Reports 2000
Large and small artery - elastin - collagen Peak Eeff (effective Young s modulus) : collagen; ~10 8, elastin; 3x10 5, smooth muscle; ~ 10 5-10 6? N/m 2
Resistance Artery Study in Human Gluteal subcutaneous biopsy Small artery studies (isobaric) Subcutaneous fat 60mmHg Park JB. 2000 dissection Peripheral resistance artery (150 ~350 µm) Structure; media to lumen ratio Function; ach and nitroprusside Mechanics -intraluminal pressure = 3-140 mmhg -lumen and media measurements
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 (%) 63-97 Endothelial Function - Ach response Vascular Stiffness - E inc vs stress LV Mass ECG/ECHO 34-58 No change 26-34 Park JB, Schiffrin EL. J Hypertens 2001;19:921
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 10 8 6 4 2 0 ** M/L<0.11 M/L 0.11
1-Year Treatment Effects of Losartan and Atenolol on Small Artery Structure and Function in Hypertension Structure Endothelium-dependent relaxation Media/Lumen ratio (%) 10 8 6 4 2 0 * Losartan before Losartan 1 year Atenolol before Atenolol 1 year * 100 80 60 40 20 0 Maximal Acetylcholine Response (%) Schiffrin and Park..Circulation 2000
Arteriosclerosis & atherosclerosis of large artery Compliant Arterio and Atherosclerosis Systole Diastole Systole Diastole Constant Stroke Volume Aorta compliant stiffened Pulse pressure
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
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
Difference of CVD prediction between systolic and diastolic BP as a function of age 1.0 SBP SV & Art. stiffness Large a. 1.0 0.5 0.5 β(sbp)-β(dbp) 0.0-0.5-1.0-1.5 DBP PVR & Neurohormone Small a. 0.0-0.5-1.0-1.5 β(sbp)-β(dbp) 25 35 45 55 65 75 Age (year) 25 35 45 55 65 75 Age (year) 2003 JNC VII Park JB 2006
Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: : a link?
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.
Systolic blood pressure, mmhg 175 150 125 100 75 50 25 0 Aldo *** *** *** Aldo+BMS Control 0 1 2 3 4 5 6 Media to lumen, % 10.0 7.5 5.0 2.5 0.0 ** + Control Aldo Aldo+BMS Experiment period, week Hypertension 2001
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. 2000 Hypertension (Modified )
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, % 5 4 3 2 1 0 ** ++ control aldo aldo+bms 3 * 2 1 0 ++ control aldo aldo+bms Control Aldo Aldo+BMS 20 10 0 * BMS (BMS 182874) ETA-selective endothelin antagonist Am J Hypertens 2002
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
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
Contents: Hypertensive Vascular Remodeling? Aldosterone on Vascular Remodeling. Aldosterone and NAD(P)H Oxidase: a link?
ROS and Vascular alterations (the courtesy from Rhian M Touyz, 2004)
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
- BBRC 2004
Effect of aldosterone on NA(D)PH oxidase activity in aldosterone-induced fibrosis Iglarz M et al. 2004 AJH
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 +
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. 2001 Hypertension Endothelin nuclear signaling Protein synthesis Cell growth ECM deposition growth factor production CARDIO- VASCULAR REMODELING Park JB. 2003
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.
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.
Role of a p47phox-containing NADPH oxidase in aldosterone-induced vascular oxidative stress and hypertrophy in mice Systolic Blood Pressure (mmhg) 160 140 120 100 80 60 40 * * 0 1 2 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
Relationship between aldosterone, and oxidative stress, inflammation, fibrosis
Aldosterone blockade and AT 1 R blockade: Trials in post-mi LV dysfunction and HF RALES EPHESUS 1.00 0.90 Probability 0.75 of survival 0.60 0.45 0.00 0 6 30% Risk reduction RR 0.70 (0.60 0.82) P < 0.001 12 18 Spironolactone 25 mg Placebo 24 30 36 22 18 Cumulative14 incidence 10 (%) 6 2 0 0 15% Risk reduction RR 0.85 (0.75 0.96) P = 0.008 Eplerenone 50 mg 6 12 18 24 30 Placebo 36 Months Months Pitt B et al. N Eng J Med. 1999;341:709-17. Pitt B et al. N Eng J Med. 2003;348:1309-21.
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
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
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