Oxidative stress-induced neuro-cardiovascular dysfunction in myocardial infarction-induced heart failure
- Myocardial infarction (MI)-associated morbidity/mortality is linked to unchecked neurohumoral excitation that eventually fuels a downward spiral of cardiac deterioration. The central nervous system (CNS) has emerged as a primary culprit in driving the neural dysfunction, although the underlying molecular mechanisms remain poorly understood. Our overall working hypothesis is that excessive production of reactive oxygen species (ROS) in key CNS circuits mediates neuro-cardiovascular dysregulation in heart failure. This hypothesis derived from our recent studies showing that gene transfer of the superoxide scavenger CuZnSOD to brain of mice in heart failure restored central neuronal excitation and sympathetic activity to normal.
Currently, we are addressing the following specific hypotheses to understand neurohumeral mechanisms underlying MI-induced heart failure:
- Oxidative stress in the subfornical organ and/or paraventricular nucleus of the brain causes autonomic, baroreflex and cardiac dysfunction in MI-induced heart failure.
- Mice genetically engineered to be hyperresponsive to stimulation of the brain renin-angiotensin system will suffer an accelerated post-MI decline to heart failure due to exacerbated central redox signaling and neuro-cardiovascular dysregulation.
- Nox2 and/or Nox4 containing NADPH oxidases are critical upstream mediators of central ROS overproduction and neuro-cardiovascular dysfunction in heart failure following MI.
- Redox-mediated activation of NFB and AP-1 in central cardiovascular networks are important downstream molecular events in the pathogenesis of MI-induced heart failure.