Silva J A, Araujo R C, Baltatu O, Oliveira S M, Tschöpe C, Fink E, Hoffmann S, Plehm R, Chai K X, Chao L, Chao J, Ganten D, Pesquero J B, Bader M
Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
FASEB J. 2000 Oct;14(13):1858-60. doi: 10.1096/fj.99-1010fje.
To evaluate the cardiovascular actions of kinins, we established a transgenic rat line harboring the human tissue kallikrein gene, TGR(hKLK1). Under the control of the zinc-inducible metallothionein promoter, the transgene was expressed in most tissues including the heart, kidney, lung, and brain, and human kallikrein was detected in the urine of transgenic animals. Transgenic rats had a lower 24-h mean arterial pressure in comparison with control rats, which was further decreased when their diet was supplemented with zinc. The day/night rhythm of blood pressure was significantly diminished in TGR(hKLK1) animals, whereas the circadian rhythms of heart rate and locomotor activity were unaffected. Induction of cardiac hypertrophy by isoproterenol treatment revealed a marked protective effect of the kallikrein transgene because the cardiac weight of TGR(hKLK1) increased significantly less, and the expression of atrial natriuretic peptide and collagen III as markers for hypertrophy and fibrosis, respectively, were less enhanced. The specific kinin-B2 receptor antagonist, icatibant, abolished this cardioprotective effect. In conclusion, the kallikrein-kinin system is an important determinant in the regulation of blood pressure and its circadian rhythmicity. It also exerts antihypertrophic and antifibrotic actions in the heart.
为了评估激肽的心血管作用，我们建立了一种携带人组织激肽释放酶基因的转基因大鼠品系，即TGR（hKLK1）。在锌诱导型金属硫蛋白启动子的控制下，转基因在包括心脏、肾脏、肺和脑在内的大多数组织中表达，并且在转基因动物的尿液中检测到了人激肽释放酶。与对照大鼠相比，转基因大鼠的24小时平均动脉压较低，当它们的饮食中补充锌时，平均动脉压会进一步降低。TGR（hKLK1）动物的血压昼夜节律明显减弱，而心率和运动活动的昼夜节律未受影响。异丙肾上腺素治疗诱导的心脏肥大显示激肽释放酶转基因具有显著的保护作用，因为TGR（hKLK1）的心脏重量增加明显较少，并且作为肥大和纤维化标志物的心房利钠肽和胶原蛋白III的表达增强程度较低。特异性激肽B2受体拮抗剂艾替班特消除了这种心脏保护作用。总之，激肽释放酶-激肽系统是血压调节及其昼夜节律的重要决定因素。它在心脏中还发挥着抗肥大和抗纤维化作用。
