ROS Signaling in Baroreeeptor and Sympathetic Neurons in Normal and Heart Failure

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The membrane properties and associated electrical excitability of afferent baroreceptor neurons (BRN) and efferent sympathetic neurons (SN) are important determinants of baroreflex sensitivity and sympathetic drive. Recent studies have shown that both BRN and SN can produce reactive oxygen species (ROS), but little is known regarding the functional role of ROS in these neurons. Our preliminary data suggest that ROS decrease excitability of BRN but increase excitability of SN, both effects promoting increases in sympathetic nerve activity and blood pressure. We propose to test the following hypotheses: ¿ ROS produced in BRN and SN during sustained neuronal activation (minutes) function as signaling molecules that modulate baroreceptor and sympathetic neuronal activity under physiological conditions. ¿ Chronic oxidative stress in a novel mouse model of combined hypercholesterolemia and hypertension contributes to autonomic/baroreflex dysregulation, and subsequent spontaneous development of heart failure and catastrophic events. ¿ BRN and SN are key sites of oxidative stress and targets of ROS-mediated dysfunction in this model of heart failure. A variety of experimental approaches will be used including assessment of ion channel function and excitability in isolated BRN and SN, viral-mediated gene transfer of siRNAs and selective peptide inhibitors of signaling molecules (e.g., CaMKII, PKC) to ganglia and neurons, integrative studies in mice, and systemic antioxidant therapies. The studies will define effective stimuli for generation of ROS (e.g., neuronal activation, angiotensin II), and the intracellular signaling pathways and ion channel targets involved in mediating ROS-dependent changes in excitability. Mice with hypercholesterolemia, hypertension, and eventual heart failure will be generated by inter-breeding hypercholesterolemic apolipoprotein E~'~ mice and hypertensive human renin-angiotensinogen double transgenic mice. Cause-and-effect relationships between oxidative stress, autonomic dysregulation, and progression to heart failure will be illuminated by implementing antioxidant therapies within specific time windows designed to prevent or reverse functional deficits. The results will advance our understanding of mechanisms regulating sympathetic activity and provide insights into optimizing antioxidant therapies for treatment of the autonomic dysregulation of heart failure. The importance of the work is underscored by the enormous public health burden presented by cardiovascular disease and the need for more effective therapies for patients with heart failure.