Heart failure (HF) is a devastating disease. Debilitation, mortality, and concomitant economic burden associated with HF all point to the need for new therapies to address this problem more effectively. Increased pro-inflammatory cytokines (PICs) in periphery and the central nervous system, particularly tumor necrosis factor-? (TNF-?), have been implicated in the pathophysiology of HF. However, anti-TNF clinical trials targeting peripheral manifestations of HF have failed to exhibit beneficial significance, indicating that the mechanisms of TNF-? have not been challenged. Our previous study discovered that TNF-? increases in cardiovascular/autonomic-related regions of the brain in a rat model of HF and contribute significantly to sympathetic excitation in that setting. More recently, our preliminary data indicated that TACE, a TNF-? converting enzyme, is upregulated in the paraventricular nucleus (PVN) of hypothalamus and subfornical organ (SFO) of the brain, and can alter cardiovascular function and sympathetic drive in HF rats. Unlike other cytokines, TNF-? is initially produced as a transmembrane protein (tmTNF-?). TACE is responsible for the cleavage of tmTNF-? to release its mature form, the soluble TNF-? (sTNF-?), to mediate inflammatory and immune responses. Further evidence indicated that sTNF-? binds predominantly to the TNF receptor 1 (TNFR1) to elicit pro-inflammatory and toxic responses and that tmTNF-? binds preferentially to the TNF receptor 2 (TNFR2) to display an anti-inflammatory and protective role. This project will underline the role of the brain TACE in TNF-??induced inflammatory mechanisms driving the neurohumoral activation in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, and biochemistry in sham-operated and HF rats, this project will determine 1) whether TACE regulates the balance between sTNF-? and tmTNF-? in SFO and PVN in HF, and what cell types are involved; 2) whether increased TACE activity and/or decreased TNFR2 expression in brain contribute to the neurohumoral excitation in HF; 3) whether inhibition of TACE or activation of TNFR2 in the brain has a beneficial effect on cardiac function and survival rate in HF. These studies will characterize a previously unrecognized role of brain TACE in neurohumoral activation in HF and will identify a novel anti-TNF target for pharmacological intervention of HF. Completion of this research project will provide important insights into the anti-cytokine therapeutic strategy in HF and may also have implications in other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.
This project examines the role of brain TACE, a TNF-? converting enzyme, in regulating neurohumoral activation and cardiac function in a rat model of systolic heart failure. These studies will lead to a better understanding of TNF-??induced central inflammatory mechanisms driving sympathetic excitation in heart failure and will shed light on the unsuccessful anti-TNF strategy targeting the peripheral magnifications of heart failure. Targeting TACE in the central nervous system is a potential anti-TNF therapeutic strategy for heart failure and may ultimately lead to improvements of pharmaceutical treatment of this devastating disease.
|Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2018) Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats. Neuroscience 381:46-58|
|Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2018) Sex Differences in the Central and Peripheral Manifestations of Ischemia-induced Heart Failure in Rats. Am J Physiol Heart Circ Physiol :|