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* To whom correspondence should be addressed. E-mail: chaoj{at}musc.edu.
Hypertension, resulting in left ventricular (LV) hypertrophy and/or fibrosis, can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. In order to investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 weeks, but had no effect from 3 to 5 weeks. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV/heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes following kallikrein gene transfer were associated with decreases in c-Jun N-terminal kinase (JNK) activation as well as transforming growth factor (TGF)-
1 and plasminogen activator inhibitor (PAI)-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide (NO) and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-1, and PAI-1 via the NO-cGMP pathway.
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