Shunguang Wei, Ph.D. - US grants

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.

Heart failure (HF) is the most common reason for hospitalization and death among those older than 65 years, and statistic is projected to grow as our population ages. The socioeconomic impact of HF on our health care system is enormous. Development of innovative approaches to the treatment of HF is therefore a top research priority. Although inflammation and immune activation have been implicated in the pathophysiology of HF over the past two decades, the progress for development of new pharmaceutical agents targeting this mechanism was stagnant, especially given that several anti-cytokine clinical trials targeting a single effector cytokine at the peripheral manifestations of HF did not produce clinical benefits. Obviously, the inflammatory mechanisms underlying the pathogenesis of HF have not been challenged. The proposed project studying a role of brain interleukin (IL)-17A (previously known as IL-17) in advancing central inflammation, sympathetic activation and cardiac dysfunction will address the need for a better understanding of the inflammatory mechanisms in HF and provide a novel anti-cytokine approach in treating this devastating disease. The research plan was developed based on the intrinsic property of IL-17A and our compelling preliminary data: 1) IL-17A is a kay inflammatory regulator bridging immune responses and tissue inflammation; 2) It boosts the expression of a broad spectrum of inflammatory mediators in the brain and in the peripheral tissue and cells; 3) Systemic and central administration of IL-17A induced dramatic and long-lasting increases in blood pressure, heart rate and renal sympathetic nerve activity to the levels not seen by other pre-inflammatory cytokines; 4) levels of IL-17A in the plasma, cerebrospinal fluid, and paraventricular nucleus of hypothalamus (PVN, a key cardiovascular and autonomic center of the brain) are higher in a rat model of HF vs. in sham-operated (Sham) animals; and 5) Its receptor, IL-17RA, is highly expressed in the PVN and substantially upregulated in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, biochemistry and neuroscience in Sham and HF rats, this project will: 1) identify the role of IL-17A in advancing central inflammation in HF; 2) determine the inflammatory mechanisms whereby IL-17A triggers sympathetic activation in HF; 3) evaluate the protective effect of central interventions targeting the IL-17A signaling, alone or in combination with other cytokines in HF. The proposed research will target a master regulator of inflammation rather than a single effector cytokine as a novel anti-cytokine strategy in treating HF, and consider the synergistic actions of multiple cytokines as a potentially more effective means of ameliorating HF. The proposed studies will characterize a previously unrecognized role of brain IL-17A in sympathetic activation and test its potential as a target in treating cardiac dysfunction of HF. Completion of this research project will provide important insights into the anti-inflammation therapeutic strategy in HF and may carry the implication for other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.