Hypertrophy and Postischemic Contractile Dysfunction in Mice Overexpressing the Active Form of Zea maize RacD in the Heart

Abstract

We investigated the effect of increased reactive oxygen species (ROS) in the heart on myocardial injury. Our hypothesis is overexpressing Rac 1 in the heart will have increased ROS generation, hypertrophy and poor contractile recovery during ischemia reperfusion (I/R). We have generated a TG mouse model that expresses the cDNA of a constitutively active mutant of Zea maize Rac‐D gene in the heart of FVB/N mice using a mouse ?‐myosin heavy chain promoter. IHC analysis confirmed the expression of Rac‐D protein in the heart of TG mice. Echocardiographic analysis showed significantly low ejection fraction in TG mice compared to control mice [20±4 (TG) vs. 62±5 (control), P<0.05]. Magnetic Resonance Imaging (MRI) study revealed a significant left ventricular hypertrophy in TG mice.Western blotting confirmed the activation of the hypertrophic signaling cascades in the heart of TG mice, both phospho‐ERK1/2 and phospho‐JNK were significantly higher in TG mice.I/R studies performed on isolated hearts demonstrated markedly poor post ischemic contractile recovery with frequent abnormal ventricular rhythms. This study shows the importance of Rac 1 in NADPH/ROS‐mediated myocardial injury during I/R. In conclusion, the Rac‐D transgenic model provides an advantage to investigate the signaling mechanisms regulating ischemic heart diseases and helps to develop therapeutic approaches for ischemic heart diseases.