Superoxide scavenging in the paraventricular nucleus (PVN) reduces sympathoexcitation and improves cardiac function following myocardial infarction

We have shown that forebrain oxidative stress is involved in the increased sympathetic output that accompanies myocardial infarction (MI)‐induced heart failure in mice. Here we hypothesized that removal of superoxide from the PVN, a brain region controlling neurohumoral drive, would normalize sympathetic output and improve cardiac function following MI. Male C57BL/6 mice received dual PVN injections (200nL) of adenovirus encoding copper‐zinc superoxide dismutase (CuZnSOD, 1×10 11 pfu/mL) or control β‐gal (0.9×10 11 pfu/mL), followed by ligation of the left anterior descending artery to cause MI. Heart function was assessed by high resolution echocardiography and sympathetic output by norepinephrine (NE) ELISA 14 days later. MI elevated PVN superoxide levels (DHE fluorescence 1.98 fold sham ± 0.21, p<0.01, n=10) which were normalized by CuZnSOD overexpression (1.09 ± 0.14, p<0.01, n=10). MI decreased ejection fraction (29.1 ± 4.2% vs sham 54.8 ± 3.7%, p<0.01, n=16) and increased left ventricle end‐volume (87.7±6.5 vs sham 48.1±2.9 μL 3 , p<0.01, n=16) which were restored by CuZnSOD (52.3 ± 4.3%, 50.7±3.3 μL 3 , p<0.01, n=11). NE levels were normalized in CuZnSOD‐treated mice (sham 200±24, MI 491±42, MI CuZnSOD 354±37 ng/mL, p<0.05, n=10–11), implicating oxidative stress in PVN in increasing sympathetic drive after MI. These data support that ROS scavenging in the PVN can improve cardiac function following MI.