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1 Nephrology, HELIOS Klinikum-Berlin, Franz Volhard Clinic and Medical Faculty of the Charite Humboldt University of Berlin, Berlin, Germany
2 Nephrology, Department of Medicine, Hannover Medical School, Hannover, Germany
3 Cardiology, Department of Cardiology, Charite Campus Mitte, Berlin, Berlin, Germany
4 Nephrology, HELIOS Klinikum-Berlin, Franz Volhard Clinic and Medical Faculty of the Charite Humboldt University of Berlin, Berlin, Germany; Cardiology, Max-Delbruck-Center for CMolecular Medicine, Berlin and Franz Volhard Clinic and Medical Faculty of theharite, Humboldt University of Berlin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: mueller{at}fvk-berlin.de.
About half of double transgenic rats (dTGR) over-expressing the human renin and angiotensinogen genes die by age 7 weeks of terminal heart failure (THF); the other (preterminal) half develops cardiac damage, but survives to week 7. The aim of our study was to elucidate the difference in cardiac gene expression of dTGR with THF compared to dTGR showing compensated cardiac hypertrophy, but not yet THF. Non-transgenic rats (SD) served as control. We also examined the effect of the AT1 receptor blocker losartan (LOS) on gene expression and cardiac injury. THF-dTGR body weight was significantly lower than all other groups. At sacrifice, THF-dTGR had blood pressures of 228±7 mm Hg; cardiac hypertrophy index 6.2±0.1 mg/g. Tissue Doppler measurements showed a reduced peak early (Ea) and late (Aa) diastolic expansion velocities in THF-dTGR indicating diastolic function (Ea<Aa). Preterminal dTGR had blood pressures of 197±5 mm Hg; cardiac hypertrophy index 5.1±0.1 mg/g; Ea<Aa. LOS-dTGR had blood pressures of 141±6 mm Hg; cardiac hypertrophy index 3.7±0.1 mg/g; Ea>Aa. For SD, blood pressure was 112±4 mm Hg; cardiac hypertrophy index 3.6±0.1 mg/g; Ea>Aa. Left ventricular total RNA was isolated for the Affymetrix system and TaqMan RT-PCR. THF-dTGR and dTGR showed an up-regulation of several hypertrophy markers and a 
/
-MHC switch to the fetal isoform. THF-dTGR (vs. dTGR) showed an up-regulation of 239 and down-regulation of 150 genes. Various genes of the mitochodrial respiratory chain and lipid catabolism were reduced. In addition, genes encoding the transcription factors (CEBP-beta, c-fos, Fra-1), coagulation (PAI-1, t-PA, uPAR-1), remodeling/repair components (HSP70, HSP27, heme oxygenase, TIMP-1), immune system (complement components, MHC class I, IL-6, HSP70) and metabolic pathway genes (GLUT1, GLUT4, Phosphofructokinase) were differentially expressed. In contrast, LOS-dTGR and SD had similar expression profiles. These data show that THF-dTGR show an altered expression profile compared to preterminal dTGR. LOS reverts the expression profiles towards normal.
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