Cardiac Angiotensin II Type 2 Receptor Activates the Kinin/NO System and Inhibits Fibrosis

Abstract

Abstract-We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT 2 receptors in cardiomyocytes attenuates Ang II-induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT 2 receptor relative to AT 1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by Ϸ45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B 2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (Ϸ2.6-fold, PϽ0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B 2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B 2 receptors were present in fibroblasts. These results suggest that stimulation of AT 2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting. Key Words: receptors, angiotensin II Ⅲ kinins Ⅲ mice Ⅲ fibrosis Ⅲ hypertrophy A ngiotensin (Ang) II is an important humoral factor responsible for cardiomyocyte hypertrophy as well as interstitial hyperplasia. 1 Both of the major Ang II receptor subtypes, AT 1 and AT 2 , are expressed in the heart. 2 The AT 2 receptor (AT 2 R) has been implicated in suppression of myocardial hypertrophy, 3-5 fibroblast proliferation, 6,7 and vascular cell hyperplasia. 8,9 However, little is known about the mechanisms by which this receptor subtype exerts such antigrowth effects and the role of the cardiac AT 2 R in cardiac diseases in vivo. Previous studies have suggested possible involvement of the bradykinin/nitric oxide (NO)/cGMP system in AT 2 R-mediated physiological functions in the rat aorta, 10 canine coronary artery, 11 a rat model of heart failure caused by myocardial infarction, 12,13 hypertrophied rat heart caused by aortic coarctation, 4 and in the kidney. 14 We have recently demonstrated that AT 2 R overexpression in vascular smooth muscle cells activates the vascular kinin system and causes vasodilation in transgenic mice. 15 However,...

Acute neurohumoral modulation of diastolic function

“…A link between AT 2 receptor signaling pathway and stimulation of endothelial bradykinin B 2 receptors (with activation of constitutive nitric oxide synthase) was already described in the heart [29]. Overall, these findings demonstrated that selective AT 2 receptor-stimulation is associated with a negative lusitropic effect modulated by the endocardial endothelium and mediated by bradykinin B 2 receptors through NO release.…”

Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

“…30,31 This occurs either directly 32 or indirectly through enhanced bradykinin formation 6,33 or increased endothelial NO synthase activity/expression. 34 Thus, AT 2 R may also favorably affect endothelial function.…”

Bradykinine et néphroprotection

“…Il a été démontré dans plusieurs modèles que la vasodilatation, dépendante de l'endothélium et induite par l'angiotensine II est fortement réduite par un antagoniste du RB2 [10]. De même, la surexpression du récepteur AT2 réduit la fibrose périvasculaire cardiaque induite par la perfusion d'angiotensine II, un effet dépendant du RB2 supprimé par un antagoniste du RB2 [11]. L'activité anti-fibrosante du récepteur AT2 ne repose toutefois pas exclusivement sur l'activation du RB2 car une stimulation de la formation de NO par le récepteur AT2 a été démontrée chez les souris n'exprimant pas le RB2 [12].…”