Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis
Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis
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DOI：
10.1161/01.hyp.0000050101.90932.14
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发表时间：
2003-01-01
期刊：
影响因子：
8.3
通讯作者：
Matsubara, H
中科院分区：
文献类型：
--
作者：
Kurisu, S;Ozono, R;Matsubara, H
我们以前已经证明，血管平滑肌细胞中的血管紧张素（Ang）II 2型受体的刺激引起缓激肽生产激活激肽原酶在转基因小鼠。本研究的目的是确定心肌细胞中AT（2）受体的过表达是否通过激肽/一氧化氮（NO）依赖性机制减轻Ang II诱导的小鼠心肌细胞肥大或间质纤维化。将Ang II（1.4mg/kg/天）或载体皮下输注到转基因小鼠和野生型小鼠中14天。转基因小鼠心脏AT（2）受体相对于AT（1）受体的数量为22%~ 37%。在转基因小鼠和野生型小鼠中，血管紧张素II引起相似的收缩压升高（大约45毫米汞柱）。通过肌细胞横截面积、左心室质量和心房利钠肽mRNA水平的增加来评估转基因小鼠和野生型小鼠的肌细胞肥大。血管紧张素II诱导显著的肌内冠状动脉血管周围纤维化，其程度在转基因小鼠中显著低于野生型小鼠。通过与缓激肽B-2受体拮抗剂HOE 140或NO合酶抑制剂L-NAME共同处理，可消除转基因小鼠血管周围纤维化的抑制作用。心肌激肽原酶活性明显升高（约2.6倍，P
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 approximate to45 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 (approximate to2.6-fold, P