Principal Investigator: Dr. Robin Davisson

Contact Information: E-mail: rld44@cornell.edu - Phone: 607-253-3537
Sponsor: American Heart Association
Grant Number: 0540114N
Title: Oxidative Stress-Induced Neuro-Cardiovascular Dysfunction in Heart Failure
Annual Direct Cost: $90,910
Project Period: 06/01/06-12/31/09

DESCRIPTION (provided by applicant): Myocardial infarction (MI) and heart failure are devastating consequences of cardiovascular disease. Their associated morbidity/mortality is linked to unchecked neurohumoral excitation that eventually fuels a downward spiral of cardiovascular 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. The overall hypothesis of this proposal is that excessive production of reactive oxygen species (ROS) in the CNS mediates neuro-cardiovascular dysregulation in heart failure. This hypothesis is in part 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. Harnessing the power of a number of our newly developed molecular tools, in combination with state-of-the-art imaging and cardiovascular analysis in a mouse model of MI-induced heart failure, we will direct our efforts toward addressing these specific hypotheses:

• Oxidative stress in key cardiovascular circuits 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.
• NADPH oxidase is a critical upstream mediator of central ROS overproduction and neuro-cardiovascular dysfunction in heart failure following MI.
• Redox-mediated activation of NFkB and AP-1 in central cardiovascular networks are important downstream molecular events in the pathogenesis of MI-induced heart failure.