title: Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis.
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 AT2 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 AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by approximately 45 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 B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (approximately 2.6-fold, P<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 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.
authors.affiliation: First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurisu
authors.forename: Ryoji
authors.initials: R
authors.lastname: Ozono
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oshima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kambe
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugino
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsuura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Teranishi
authors.forename: Osamu
authors.initials: O
authors.lastname: Iba
authors.forename: Katsuya
authors.initials: K
authors.lastname: Amano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D003331:Coronary Vessels / Q000473:pathology; D005110:Extracellular Space; D005355:Fibrosis; D006352:Heart Ventricles / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018002:Receptors, Bradykinin / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D007610:Kallikreins; D001920:Bradykinin