Protective actions of human tissue kallikrein gene in transgenic rat hearts

In this study, we used an experimental model of cardiac hypertrophy to explore the role of the kallikrein-kinin system (KKS) in cardiac protection in transgenic rats harboring the human tissue kallikrein gene, TGR(hKLK1). Tissue kallikrein cleaves low-molecular-weight kininogen to produce kinin peptides, which bind to kinin receptors and trigger a wide spectrum of biological effects. The transgene, under the control of the zinc-inducible metallothionein promoter, was expressed in most tissues including the heart, kidney, lung and brain. These animals were subjected to treatment with thyroid hormone in order to promote cardiac hypertrophy. Induction of cardiac hypertrophy revealed a marked protective effect caused by the expression of the kallikrein transgene, evidenced by the significantly reduced cardiac weight gain and the lower enhancement in the cardiac expression of atrial natriuretic peptide and collagen III, markers for hypertrophy and fibrosis, respectively. In conclusion, our data show that expression of tissue kallikrein exerts antihypertrophic and antifibrotic actions in the heart.