Mapping long‐term transactivation of redox‐sensitive AP‐1 in the paraventricular nucleus (PVN) following myocardial infarction (MI) using in vivo bioluminescence

Abstract

Heart failure is characterized by sustained sympathoexcitation and deteriorating cardiac function. We have recently shown that excessive redox signaling in the PVN contributes to these changes, however the molecular mechanisms remain poorly understood. We hypothesized that chronic oxidative stress in the PVN causes activation of the redox‐sensitive transcription factor Activator Protein 1 (AP‐1) following MI. To test this, C57 mice were given bilateral PVN injections of adenoviruses encoding firefly luciferase downstream of AP‐1 (AdAP1‐Luc) in combination with either the ROS scavenger superoxide dismutase (AdSOD) or control (AdLacZ). Two wks after gene transfer, mice underwent MI (LAD ligation) or sham surgery and measurement of AP‐1 activation for 6 weeks by in vivo bioluminescence. MI caused a significant increase in AP‐1 activation in the PVN between 1 and 2 wks post‐ligation (AdLacZ 181018 ± 45474 vs. sham 73036 ± 12462 photons/sec; n=5, p<0.05). Interestingly, MI‐induced AP‐1 activation was abolished in MI mice treated with AdSOD (79314 ± 12375 photons/sec, p<0.05, n=5). Echocardiography at 2wks post‐MI showed significantly reduced ejection fractions in LacZ‐treated mice (23±3% vs 57±4%, p<0.05, n=5) which was markedly improved with AdSOD treatment (43±6%, p<0.05, n=5). These data suggest that ROS‐mediated activation of AP‐1 in the PVN may contribute to decreased cardiac function after MI.