Stellate Ganglia Nrf2 Signaling and Enhanced Cardiac Sympathetic Tone in Chronic Heart Failure

Abstract Excessive oxidative stress has been shown to be a potent pathophysiological mediator in multiple disease states. Cardiac and peripheral sympathetic nerve activity is increased in chronic heart failure, in part, due to augmented neural inflammation and oxidative stress. Importantly, several major antioxidant enzymes and molecules are

decreased in the cytosol and mitochondria of pre-sympathetic neurons in chronic heart failure. A major regulator of these antioxidant molecules is the transcription factor, Nrf2. Previous studies from our laboratories have shown a reduction in Nrf2 in heart failure. Genetic knock down of Nrf2 in the rostral ventrolateral medulla of normal mice

results in significant sympatho-excitation and hypertension. On the other hand, overexpression of Nrf2 results in sympatho-inhibition in mice with chronic heart failure along with a reduction in oxidative stress and an increase in several antioxidant enzymes. In order to determine if this mechanism plays a role in cardiac arrhythmogenesis

in the post myocardial infarction (MI) chronic heart failure model we propose here to evaluate the role of Nrf2 in the stellate ganglia, a source of major sympathetic outflow to the heart. Three specific aims are proposed. Specific Aim 1: We will determine the time-course changes in neural inflammation-Oxidative stress-Nrf2

signaling in the SG post MI. We will evaluate message and protein for the key molecules involved in maintaining redox homeostasis in the SG, namely the Nrf2/Keap1 system and its target antioxidant enzymes, including NQO1, HO1, Catalase, SOD and glutathione peroxidase. We will also assess neural inflammation in the SG by

measuring macrophage infiltration and pro-inflammatory cytokines. Correlations will be made between levels of Nrf2 and cardiac sympathetic tone across a wide range of cardiac function. Specific Aim 2: We will determine if selective knockdown and overexpression of Nrf2 in the SG alters cardiac sympathetic tone in normal and CHF

animals by altering ganglionic neuronal excitability. Using Nrf2 and Keap1 floxed mice we will evaluate antioxidant enzyme expression, redox homeostasis, inflammation and arrhythmia incidence. These molecular alterations induced by Nrf2 will be evident in SG cell action potential generation. Specific Aim 3: We will

determine if pharmaceutic manipulation of Nrf2 signaling in the SG by local SG delivery of micelle conjugated dynamic hydrogels with encapsulation of two Nrf2 activators (i.e., Curcumin and sulforaphane) reduces arrhythmogenesis and improves cardiac function in the post-MI rats. We hypothesize that the redox status and

electrophysiological activity of SG neurons in CHF rats will be partially restored following treatment with Nrf2 activators. Furthermore, these effects will be abolished or attenuated in mice with stellate ganglia Nrf2 deficiency. We believe that this proposed research will lay a solid scientific foundation for developing a new therapies for

the patients with CHF.