Effects of Central Intervention of Tumor Necrosis Factor‐α Converting Enzyme (TACE) on Neuroinflammation and Cardiac Function in Heart Failure

Abstract

Central nervous system inflammation has been implicated in the neurohumoral activation and disease progression in experimental animal models of heart failure (HF). The pro‐inflammatory cytokine tumor necrosis factor‐α (TNF‐α) increases in cardiovascular/autonomic brain regions including the paraventricular nucleus of the hypothalamus (PVN) and subfornical organ (SFO), and contributes significantly to the augmented sympathetic nerve activity in HF. TNF‐α is initially synthesized as a membrane bound protein that is proteolytically cleaved by TNF‐α converting enzyme (TACE), also known as a disintegrin and metalloprotease 17 (ADAM17), to become the fully functional inflammatory mediator. Our previous study demonstrated that TACE has elevated expression in the PVN and SFO and mediates TNF‐α‐induced sympathetic excitation and hemodynamic responses in HF rats. However, whether inhibition of TACE in the brain has a protective effect on central inflammation and cardiac function in HF remains unclear. We hypothesized that inhibition of TACE activity in the brain reduces central inflammation and improves left ventricular (LV) function during HF. Adult male Sprague‐Dawley rats were studied 4–5 weeks after induction of HF by coronary artery ligation. TACE activity was chronically inhibited specifically in the brain by infusion of the TACE inhibitor TAPI‐1 (30μg/day) via an osmotic minipump connected to an intracerebroventricular (ICV) cannula. Treatment with TAPI‐1 or vehicle began immediately following the myocardial infarction. At the end of experiments, LV function was assessed by echocardiography and tissues were collected for molecular analysis. In HF rats‐treated with TAPI‐1, the LV ejection fraction (26.8±0.9% vs 34.8±6.4%) was improved, although this did not reach statistical significance vs. HF treated with vehicle. Wet lung weight to body weight ratio also showed a trend towards being improved in TAPI‐1 treated animals (6.3±0.3mg/g vs. 4.8±0.4mg/g, vehicle vs. TAPI‐1, p=0.32). Additionally, TAPI‐1 treatment significantly decreased mRNA levels of proinflammatory mediators including TNF‐α, IL‐1β, and TACE in the SFO (TNF‐α: 0.28±0.10, p<0.05; IL1‐β: 0.25±0.11, p>0.05; TACE: 0.68±0.14, p<0.05, fold change vs. vehicle) and resulted in a trend toward reduced levels of these measurements in the PVN (TNF‐α: 0.52±0.13, p=0.24; IL1‐β: 0.58±0.11, p=0.21; TACE: 0.87±0.11, p=0.43, fold change vs. vehicle). TNF‐α expression was also reduced in both the superior cervical (0.35±0.07, p<0.05, fold change vs. vehicle) and stellate ganglia (0.44±0.14, p<0.05 fold change vs. vehicle). Taken together, these data suggest that central inhibition of TACE activity diminishes the inflammatory state in the brain and improve cardiac function in HF.