Activation of angiotensin II type‐1 receptors stimulates microglial production of pro‐inflammatory cytokines in hypothalamic paraventricular nucleus of heart failure rats

Abstract

Activated microglia produce pro‐inflammatory cytokines, which contribute to sympathetic activity in heart failure (HF). Microglia express angiotensin (ANG) II type‐1 receptors (AT1R), an important component of the renin‐angiotensin system. However, the relationships between the renin‐angiotensin system, activation of microglia and increased pro‐inflammatory cytokines in key cardiovascular regulatory centers of the brain has not been fully elucidated. We hypothesized that activation of AT1R mediate microglial release of pro‐inflammatory cytokines in the hypothalamic paraventricular nucleus (PVN) in HF. Rats underwent coronary ligation to induce HF or sham surgery. HF rats received a 4 week intracerebroventricular infusion of vehicle, the microglial inhibitor minocycline or the AT1R antagonist losartan. Compared with sham, vehicle‐treated HF rats had increased (P<0.05) microglial marker CD68 and Emr1 mRNA, and augmented tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), cyclooxygenase‐2 (COX‐2) and AT1R mRNA in PVN. Minocycline‐treated HF rats had less CD68 and Emr1 mRNA and reduced TNF‐α, IL‐1β and COX‐2 but not AT1R mRNA in PVN. Losartan‐treated HF rats also had less Emr1 mRNA and reduced TNF‐α, IL‐1β and COX‐2 in PVN, as well as reduced AT1R mRNA. These results suggest that activation of AT1R contributes to microglial production of pro‐inflammatory cytokines in the PVN of HF rats.