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.
This research project is to investigate the novel role of a kay inflammatory mediator interleukin-17A in the brain in promoting central inflammation, neurohumoral activation and cardiac dysfunction in an experimental model of systolic heart failure. These studies will lead to a better understanding of central inflammatory mechanisms underlying sympathetic excitation in heart failure and provide novel insights into the anti-cytokine strategies in the treatment of heart failure. Targeting the brain interleukin-17A to reduce sympathetic activation is a potential anti-inflammation therapeutic approach and may ultimately lead to clinical improvements of this devastating disease.
