Brain Tumor Necrosis Factor‐α Converting Enzyme Contributes to Sympathetic Activation in Heart Failure Rats
Authors: Wei Shun‐Guang , Yu Yang , Weiss Robert M. , Felder Robert B. 
Published: November 2023

Production of the pro‐inflammatory cytokine tumor necrosis factor‐α (TNF‐α) increases in cardiovascular/autonomic regions of the brain in heart failure (HF), and TNF‐a contributes significantly to the augmented sympathetic nerve activity in that setting. TNF‐α is initially produced as a transmembrane protein (tmTNF‐α). The soluble form of TNF‐α that binds predominantly to TNF‐α receptor 1 to play an excitatory/toxic role is cleaved from tmTNF‐α by tumor necrosis factor‐α converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17). In HF, the augmented level of the TNF‐α in the brain and circulation suggests an increase in this shedding process. The present study sought to determine whether TACE is upregulated in the subfornical organ (SFO) and hypothalamic paraventricular nucleus (PVN), two key cardiovascular and autonomic brain centers, in rats with ischemia‐induced HF, and whether increased TACE activity contributes to the increased sympathetic nerve activity in HF. Adult male Sprague‐Dawley rats were studied 4–5 weeks after induction of HF by coronary artery ligation or sham operation (SHAM). The mRNA levels of TACE measured by real time PCR were significantly (p<0.05*) elevated in the SFO (2.5 fold*) and PVN (2.2 fold*) of HF (n=6) compared with SHAM rats (n=6). Confocal microscopy revealed that the immunoreactivity of TACE was also increased in the SFO and PVN in HF compared with SHAM animals. In urethane‐anesthetized HF rats (n=5), intracerebroventricular (ICV) injection of recombinant TACE (300 ng) induced long‐lasting increases in mean arterial pressure (MAP, mmHg: 10.6± 0.5*), heart rate (HR, bpm: 37.4 ± 2.7*) and renal sympathetic nerve activity (RSNA, % change: 41.8±4.5*) with peak responses at 3–5 hours after the injection, whereas in SHAM rats (n=5), ICV TACE induced only a small increase in MAP (5.3±0.4*), HR (12.3±1.0*) and RSNA (15.1±1.1*) that peaked at 10–15 min and returned to baseline within 30 min. In the HF rats, ICV pretreatment with the TNF‐α inhibitor SPD304 (5μg) eliminated the TACE‐induced large long‐lasting MAP, HR and RSNA responses, but mild early responses similar to those of the SHAM rats persisted. ICV SPD304 did not block TACE‐induced early MAP, HR and RSNA responses in SHAM rats. The ICV TACE inhibitor TAPI (5μg) elicited a similar drop in MAP (6.3± 0.7* vs 6.8 ± 0.8*) in HF (n=5) and SHAM (n=5) rats, but an exaggerated (*) reduction in HR (21.6 ± 2.9* vs 12.1 ± 2.3*) and RSNA (32.4 ± 4.1* vs 15.3 ± 3.1*) in HF compared with SHAM rats. These data demonstrate that TACE is up‐regulated in the brain and contributes to TNF‐α‐induced sympathetic activation in HF. This study suggests that TNF‐α ectodomain shedding by TACE is an important inflammatory mechanism contributing to sympathetic excitation in HF and is a potential target for therapeutic intervention.

Support or Funding Information

Supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, and by R01HL073986 (to RBF)