Tumor Necrosis Factor‐α Receptor 1 (TNFR1) Knockdown in Subfornical Organ (SFO) Attenuates Central Expression of Excitatory Mediators and Ameliorates Peripheral Manifestations of Heart Failure in Rats after Myocardial Infarction

Myocardial infarction (MI)‐induced heart failure (HF) is a systemic inflammatory state characterized by increased circulating proinflammatory cytokines (PICs). Circulating PICs up‐regulate inflammation and renin‐angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and the progression of HF. We recently demonstrated that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood–brain barrier, is a predominant site in the brain at which circulating PICs act to elicit cardiovascular and sympathetic responses. Here we tested the hypothesis that tumor necrosis factor‐α receptor1 (TNFR1) knockdown in the SFO would modulate the MI‐induced expression of excitatory mediators in the SFO and downstream in the hypothalamic paraventricular nucleus (PVN) that mediate hemodynamic and sympathetic responses, and would ameliorate the peripheral manifestations of HF after MI. Rats received SFO microinjections of a TNFR1 shRNA or scrambled shRNA lentiviral vector carrying green fluorescent protein (GFP), or vehicle. One week later, transfection potential of the lentiviral vector was examined in some rats receiving SFO TNFR1 shRNA; other rats underwent coronary ligation to induce HF confirmed by echocardiography, or a sham operation. One week after SFO microinjections of TNFR1 shRNA, GFP fluorescence was visualized in the SFO but not in other brain areas. Four weeks after MI, HF+vehicle rats had increased mRNA of TNFR1, NF‐κB p65, cyclooxygenase (COX)‐2, angiotensin II type 1 receptor (AT1R) and c‐fos, and decreased mRNA of IkB‐α in both SFO and PVN, compared with SHAM+vehicle rats. HF+TNFR1 shRNA rats, but not HF+scrambled shRNA rats, had reduced mRNA of TNFR1 in the SFO, associated with decreased mRNA of NF‐κB p65, COX‐2, AT1R and c‐fos and elevated mRNA of IkB‐α not only in SFO but also in PVN. HF+vehicle rats also had increased plasma norepinephrine levels, lung/body weight and right ventricle/body weight ratios, which were attenuated in HF+ TNFR1 shRNA but not in HF+scrambled shRNA rats. The results suggest that HF‐induced increases in circulating TNF‐α act upon TNFR1 in the SFO to upregulate excitatory mediators in the SFO and downstream in the PVN, contributing to sympathetic excitation and cardiac dysfunction in HF. TNFR1 in the SFO may be a novel target for therapeutic intervention in inflammatory cardiovascular conditions like heart failure and hypertension. Support or Funding Information Supported by NIH Grants HL‐073986 and HL‐096671 and Department of Veterans Affairs.