Disruption of central antioxidant property of nuclear factor erythroid 2-related factor 2 worsens circulatory homeostasis with baroreflex dysfunction in heart failure

Heart failure is defined as a disruption of circulatory homeostasis. We have demonstrated that baroreflex dysfunction strikingly disrupts circulatory homeostasis. Moreover, previous many reports have suggested that central excess oxidative stress causes sympathoexcitation in heart failure. However, the central mechanisms of baroreflex dysfunction with oxidative stress has not been fully clarified. Our hypothesis was that the impairment of central antioxidant property would worsen circulatory homeostasis with baroreflex dysfunction in heart failure. As the major antioxidant property in the brain, we focused on nuclear factor erythroid 2-related factor 2 (Nrf2; cytoprotective transcription factor). Hemodynamic and baroreflex function in conscious state were assessed by the radio-telemetry system. In the heart failure treated with intracerebroventricular (ICV) infusion of angiotensin II type 1 receptor blocker (ARB), sympathetic activation and brain oxidative stress were significantly lower, and baroreflex sensitivity and volume tolerance were significantly higher than in heart failure treated with vehicle. ICV infusion of Nrf2 activator decreased sympathetic activation and brain oxidative stress, and increased baroreflex sensitivity and volume tolerance to a greater extent than ARB. In conclusion, the disruption of central antioxidant property of Nrf2 worsened circulatory homeostasis with baroreflex dysfunction in heart failure.