Chronic heart failure (CHF) affects a growing number of Americans. This disease is one of the leading causes of death and disability in the developed world. In order to develop new therapies for this disorder a comprehensive understanding of the pathogenesis and mechanisms behind CHF is critically important. Activation of the sympathetic nervous system is almost pathognomonic of CHF. Over the past 16 years we have investigated the central origins of sympatho-excitation in CHF. We have focused on the brain renin- Angiotensin II system with specific emphasis on the Angiotensin Type 1 receptor (AT1R) and its role in the generation of oxidative stress. We have shown that the transcriptional regulation of AT1R expression is mediated by NFkB in addition to several other downstream transcription factors in tissue extracted from the rostral ventrolateral medulla (RVLM). In the current project we focus on a new and potentially important mechanism in the generation of neuronal oxidative stress in the CHF state. We propose that the transcription factor Nrf2 is decreased in RVLM tissue from CHF animals. Importantly, we propose that the decrease in Nrf2 and its effects on antioxidant enzyme transcription is mediated, in part, by competition with NFkB for binding to the CREB binding protein (CBP) in the nucleus. We also propose that influences external to the cell such as exercise training and the balance between ACE and ACE2 may be important modulators of Nrf2 and oxidative stress in CHF. We will use rat and mouse CHF models. Novel transgenic mouse models will be used to address four specific aims.
Specific Aim 1 will determine the role of Nrf2 in the regulation of oxidative stress in the RVLM and its impact on sympatho-excitation in CHF. We hypothesize that a decrease in Nrf2 in the RVLM contributes to increased oxidative stress and sympathetic nerve activity of animals with CHF.
Specific Aim 2 will determine the relationships between Nrf2 and NFkB on the regulation of oxidative stress and AT1R expression in the RVLM of animals with CHF. We hypothesize that increased binding to CBP by NFkB in the RVLM of animals with CHF will result in an upregulation of AT1R and increased oxidative stress and contributes to sympatho-excitation. In addition, we hypothesize that upregulation of Nrf2 will displace NFkB from CBP thus contributing to a decrease in AT1R and an upregulation of antioxidant enzymes.
Specific Aim 3 will demonstrate that ExT decreases oxidative stress, AT1R expression, sympathetic nerve activity and RVLM discharge by a Nrf2-dependent mechanism in CHF. We hypothesize that ExT reduces Nrf2 ubiquitination and reduces the NFkB arm of this pathway.
Specific Aim 4 will determine if ACE2 reduces oxidative stress in the RVLM by activation of Nrf2. In addition, we will show that overexpression and knockdown of ACE2 in novel mouse models alters the effects of ExT on Nrf expression and activity. These studies will be thematically interactive with Projects 1and 3.
Chronic heart failure is a growing concern as the aging population of the United States increases. New strategies in the treatment of heart failure must be developed. This project is important and highly relevant to the heart failure epidemic in that it addresses a relatively neglected area of patho-physiology, namely sympathetic nerve activation and the role of central oxidative stress. We will investigate the molecular and integrative mechanisms by which neuronal oxidative stress is regulated in heart failure. These studies will uncover new potential central targets for therapy in the heart failure state.
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