gms | German Medical Science

Seven to 8-week old double transgenic rats (dTGR) overexpressing the human renin and angiotensinogen genes die of terminal heart failure (THF) and cachexia. To elucidate the mechanisms of angiotensin (Ang) II-induced cardiac injury, we analyzed gene expression patterns in THF-dTGR and compared these rats with preterminal dTGR, losartan-treated (LOS)-dTGR and non-transgenic rats (SD). Body weight of THF-dTGR was significantly lower than all other groups. At sacrifice, THF-dTGR had blood pressures of 228±7 mm Hg; cardiac hypertophy index 6.2±0.1 mg/g; echocardiography E<A; and albuminuria 21±3 mg/d. Preterminal dTGR had blood pressures of 197±5 mm Hg; cardiac hypertrophy index 5.1±0.1 mg/g; E<A; and albuminuria 17±3 mg/d. LOS-dTGR had blood pressures of 141±6 mm Hg; cardiac hypertrophy index 3.7±0.1 mg/g; E>A; and albuminuria 1±0.2 mg/d. For SD blood pressure was 112±4 mm Hg; cardiac hypertrophy index 3.6±0.1 mg/g; E>A; and albuminuria 0.2±0.02 mg/d. Total RNA of left ventricular heart tissue was isolated and the Affymetrix system was used. THF-dTGR (vs. other groups) showed an upregulation of various genes (altered >factor 2), which could be grouped into transcription factors (CEBP-beta, c-fos), coagulation (PAI-1), remodeling components (TIMP-1, lysyl oxidase), eicosanoid synthesis (lipoxygenase, cyclooxygenase), signal transduction (Rab-2, adenylate cyclase activating polypeptide-1), heat shock proteins (HSP70, HSP27, Heme oxygenase), apoptosis (bax, bcl-2, ass X protein), oxidized low density lipoprotein receptor 1, CYP family (CYP3a2, CYP3a18, CYP2b15, CYP2c23, CYP7a1, CYP2c7) and ESTs. Several hypertrophy markers were elevated in rats preterminal dTGR compared to LOS-dTGR and SD. LOS-dTGR and SD had similar expression profiles. These data show that THF-dTGR show an altered expression profile compared to preterminal dTGR. AT1 receptor blockade reverts the expression profiles to normal.