Yang Yu, Shun-Guang Wei, Robert M Weiss, Robert B Felder

In systolic heart failure (HF), circulating proinflammatory cytokines upregulate inflammation and renin-angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and cardiac dysfunction. Important among these is the subfornical organ (SFO), a forebrain circumventricular organ that lacks an effective blood-brain barrier and senses circulating humors. We hypothesized that the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1) in the SFO contributes to sympathetic excitation and cardiac dysfunction in HF rats. Rats received SFO microinjections of a TNFR1 shRNA or a scrambled shRNA lentiviral vector carrying green fluorescent protein, or vehicle. One week later, some rats were euthanized to confirm the accuracy of the SFO microinjections and the transfection potential of the lentiviral vector. Other rats underwent coronary artery ligation (CL) to induce HF or a sham operation (Sham). Four weeks after CL, vehicle- and scrambled shRNA-treated HF rats had significant increases in TNFR1 mRNA and protein, NF-κB activity, mRNA for inflammatory mediators, RAS components and c-Fos protein in the SFO and downstream in the hypothalamic paraventricular nucleus (PVN), along with increased plasma norepinephrine levels and impaired cardiac function, when compared with vehicle-treated Sham rats. In HF rats treated with TNFR1 shRNA, TNFR1 was reduced in SFO but not PVN, and all other abnormalities were ameliorated in SFO and PVN. Sham rats had none of the abnormalities observed in HF rats, and treatment with TNFR1 shRNA had no effects. These results suggest a key role for TNFR1 in the SFO in the pathophysiology of systolic HF.