Oxidative stress in the RVLM mediates sympathetic hyperactivity induced by circadian disruption. (20th November 2022) - Duan, Wei
Highlights: Circadian rhythms have a considerable impact on the daily functions, including maintaining BP and autonomic nervous system homeostasis. Disruption of circadian rhythms promotes sympathetic hyperactivity. Oxidative stress in the RVLM mediates sympathetic hyperactivity induced by circadian disruption, which is possibly associated with down-regulation of Nrf2/HO1/NQO1 signaling. Abstract: Circadian rhythm plays a significant role in maintaining the function of the cardiovascular system. Emerging studies have demonstrated that circadian disruption enhances the risk of cardiovascular diseases by activating the sympathetic nervous system; however, the underlying mechanisms remain unknown. Therefore, this study aimed to clarify the role of oxidative stress in the rostral ventrolateral medulla (RVLM) in sympathetic hyperactivity induced by circadian disruption. Rats were randomly divided into two groups: the normal light and dark (LD) group and the circadian disruption (CD) group. Sympathetic nerve activity of rats was assessed by recording renal sympathetic nerve activity (RSNA) and indirect methods such as plasma level of norepinephrine (NE). The level of oxidative stress in the RVLM was detected by dihydroethidium probes. Moreover, the expression levels of the oxidative stress-related proteins in the RVLM were detected by Western blotting. Circadian disruption significantly increased blood pressure (BP), RSNA, and plasma levels of NE. Compared to the LD group, the CD group exhibited a more significant depressor response to i.v. hexamethonium bromide, a ganglionic blocker. Furthermore, the reactive oxygen species (ROS) production in the RVLM of rats with circadian disruption was significantly increased. In addition, BP and RSNA of rats with circadian disruption exhibited a greater decrease in the effects of microinjection of tempol, a superoxide scavenger, into the RVLM, compared to artificial cerebrospinal fluid (aCSF). Further investigation of the molecular mechanism by Western blotting showed that nuclear factor-erythroid-2-related factor 2 (Nrf2)/heme oxygenase 1 (HO1)/NAD(P)H: quinone oxidoreductase 1 (NQO1) signaling was down-regulated in the RVLM of circadian disruption rats. These data suggest that oxidative stress in the RVLM mediates sympathetic hyperactivity induced by circadian disruption and possibly by down-regulating Nrf2/HO1/NQO1 signaling.