Brain endoplasmic reticulum stress mediates sympathetic and hemodynamic responses to blood‐borne TNF‐α in rats (1130.14)

Abstract

The pro‐inflammatory cytokine tumor necrosis factor (TNF)‐ α acts upon the CNS to augment sympathetic drive in normal and pathophysiological conditions, including heart failure. The underlying mechanisms are poorly understood. We hypothesized that TNF‐ α induces endoplasmic reticulum (ER) stress in the brain, upregulating inflammatory mechanisms that drive sympathetic activity. In anesthetized rats, a centrally directed intracarotid artery (ICA) injection of TNF‐α (0.5 µg/kg) increased (p<0.05, vs baseline) renal sympathetic nerve activity, mean blood pressure and heart rate. These responses were attenuated by continuous intracerebroventricular (ICV) infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 5 µg/hr). ICA TNF‐α induced molecular markers of ER stress, reactive oxygen species (ROS), NF‐кB, cyclooxygenase‐2 (COX‐2) and phosphorylation of p44/42 and p38 mitogen‐activated protein kinase (MAPK) in the subfornical organ (SFO), a CNS site at which circulating proinflammatory cytokines act to elicit sympathetic responses. TUDCA significantly reduced TNF‐α induced indicators of ER stress, phosphorylation of p44/42 and p38 MAPK and NF‐кB and COX‐2 activity in SFO, but not ROS generation. The data suggest that ER stress induced in brain tissues by blood‐borne TNF‐α contributes to central inflammatory mechanisms driving sympathetic excitation, likely via MAPK and NF‐кB signaling.Grant Funding Source: supported by NIH Grants HL‐073986 and HL‐096671 and the Department of Veterans Affairs