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Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene
Author(s) -
Silva José-A.,
Araujo Ronaldo C.,
Baltatu Ovidiu,
Oliveira Suzana M.,
Tschöpe Carsten,
Fink Edwin,
Hoffmann Sigrid,
Plehm Ralph,
Chai Karl X.,
Chao Lee,
Chao Julie,
Ganten Detlev,
Pesquero João B.,
Bader Michael
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.99-1010fje
Subject(s) - endocrinology , medicine , kallikrein , kinin , transgene , blood pressure , muscle hypertrophy , biology , genetically modified mouse , circadian rhythm , bradykinin , fibrosis , receptor , gene , biochemistry , enzyme
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.