Angiotensin II Type la Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats

Inflammation in the hypothalamic paraventricular nucleus (PVN) contributes to neurohumoral excitation and its adverse consequences in systolic heart failure (HF). The stimuli that trigger inflammation in the PVN in HF are not well understood. Angiotensin II (Angll) has pro-inflammatory effects, and circulating levels of Angll increase in HF. The subfornical organ (SFO), a circumventricular structure that lacks an effective blood-brain barrier and senses circulating Angll, contains PVN-projecting neurons. We hypothesized that activation of Angll type 1a receptors (AT(1a)R) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for AT(1a)R, a scrambled shRNA, or vehicle. One week later, some rats were euthanized to confirm the transfection potential and knockdown efficiency of the shRNA. Others underwent coronary artery ligation to induce HF or a sham coronary artery ligation (Sham). Four weeks later, HF rats that received the scrambled shRNA had increased mRNA in SFO and PVN for AT(1a)R, inflammatory mediators and indicators of neuronal and glial activation, increased plasma levels of Angll, tumor necrosis factor-alpha, norepinephrine and arginine vasopressin, and impaired cardiac function, compared with Sham rats that received scrambled shRNA. The central abnormalities were ameliorated in HF rats that received AT(1a)R shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received AT(1a)R shRNA had reduced SFO AT(1a)R mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of AT(1a)R in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.