Abstract 1503: Genetic Ablation of Angiotensin II Type1a Receptor Has a Beneficial Effect on Diabetes-induced Cardiomyopathy by Expressing Heat Shock Proteins and by Inhibiting Apoptosis
Background: We reported previously, diabetes (DM)-induced cardiac dysfunction was ameliorated in angiotensin II type 1a receptor (AT1aR) knockout mice. Growing evidence suggests that the pathogenesis of DM-induced cardiac dysfunction includes the development of apoptosis, which is induced by oxidative stress and by suppressed expression of heat shock proteins (Hsp) that have a protective role against stress-induced cardiomyocyte injury. We attempted to test the hypothesis that renin-angiotensin system (RAS) was involved in these mechanisms.
Methods: DM was induced in 100 male wild-type (WT) or AT1aR knockout mice (KO) by a single injection of streptozotocin (STZ, 200 mg/kg BW ip). Hemodynamic study using echocardiography and catheter-tip manometer, morphological and molecular study were performed 6 weeks after STZ or vehicle injection. To assess apoptosis, tissue sections from the mid-left ventricle (LV) were stained with TUNEL staining.
Results: In STZ-treated WT (WT-DM), LV ejection fraction was lower by 21%, and negative dP/dt was lower by 27% than vehicle-treated WT (WT-C). There were no differences between STZ-treated KO (KO-DM) and vehicle-treated KO (KO-C). The mRNA level of NADPH oxidase (p47phox) in the LV was 2.6-fold higher (p=0.047) and the mRNA level of glutathione peroxidase (GPx) was 1.6-fold higher in WT-DM (p=0.039) than WT-C, but there were no differences in KO groups. The mRNA and protein levels of Hsp70 were downregulated by 34% (p=0.03) and by 32% (p=0.022) in WT-DM, and Hsp110 mRNA expression was also downregulated by 56% in WT-DM (p=0.03), whereas there were no differences in KO groups. Hsp70 mRNA expression was significantly correlated with −dP/dt (r=−0.41, p=0.049). Hsp110 mRNA expression was closely correlated with +dP/dt (r=0.55, p=0.02), −dP/dt (r=−0.61, p=0.009) and LV weight (r=0.58, p=0.003). The number of TUNEL-positive cells was increased in WT-DM compared with WT-C (3.37 ± 0.40 vs. 1.97 ± 0.27 /103 nuclei, p=0.027). But there were no differences between KO-DM and KO-C (2.15 ± 0.48 vs. 1.66 ± 0.13 /103 nuclei).
Conclusions: The beneficial effect of the RAS blockade on DM-induced cardiac dysfunction is associated with attenuation of apoptosis through mechanisms involving oxidative stress and Hsp expression.