Hypothalamic Paraventricular Nucleus Hydrogen Sulfide Exerts Antihypertensive Effects in Spontaneously Hypertensive Rats via the Nrf2 Pathway

Background: Hydrogen sulfide (H₂S) is widely distributed throughout the nervous system with various antioxidant and anti-inflammatory properties. Hypertension involves an increase in reactive oxygen species (ROS) and inflammation in the hypothalamic paraventricular nucleus (PVN). However, it is unclear how H₂S in PVN affects hypertension. Methods: Our study used spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, microinjected with adeno-virus-associated virus (AAV)-CBS (cystathionine beta-synthase overexpression) or AAV-ZsGreen in bilateral PVN, or simultaneously injected with virus-carrying nuclear factor erythroid 2-related factor 2 (Nrf2)-shRNA for 4 weeks. Blood pressure (BP) and plasma noradrenaline level were detected, and the PVN was collected. Finally, levels of CBS, H₂S, Nrf2, Fra-LI, ROS, gp91^phox, p47^phox, superoxide dismutase 1, interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α, tyrosine hydroxylase, and glutamate decarboxylase 67 were measured. Results: We found that AAV-CBS increased H₂S in the PVN, and BP, neuronal activation, oxidative stress, and inflammation of PVN were substantially reduced. Furthermore, endogenous H₂S in the PVN activated Nrf2 and corrected the PVN’s imbalance of excitatory and inhibitory neurotransmitters. However, Nrf2 knockdown in the PVN was similarly observed to abolish the beneficial effect of H₂S on hypertension. Conclusions: The findings imply that endogenous H₂S in SHR PVN is reduced, and PVN endogenous H₂S can alleviate hypertension via Nrf2-mediated antioxidant and anti-inflammatory effects.