Asprosin in the Paraventricular Nucleus Induces Sympathetic Activation and Pressor Responses via cAMP-Dependent ROS Production

Abstract

Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This study was designed to determine the roles and underlying mechanisms of asprosin in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male adult SD rats under anesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded, and PVN microinjections were performed bilaterally. Asprosin mRNA and protein expressions were high in the PVN. The high asprosin expression in the PVN was involved in both the parvocellular and magnocellular regions according to immunohistochemical analysis. Microinjection of asprosin into the PVN produced dose-related increases in RSNA, MAP, and HR, which were abolished by superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), and NADPH oxidase inhibitor apocynin. The asprosin promoted superoxide production and increased NADPH oxidase activity in the PVN. Furthermore, it increased the cAMP level, adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in the PVN. The roles of asprosin in increasing RSNA, MAP, and HR were prevented by pretreatment with AC inhibitor SQ22536 or PKA inhibitor H89 in the PVN. Microinjection of cAMP analog db-cAMP into the PVN played similar roles with asprosin in increasing the RSNA, MAP, and HR, but failed to further augment the effects of asprosin. Pretreatment with PVN microinjection of SQ22536 or H89 abolished the roles of asprosin in increasing superoxide production and NADPH oxidase activity in the PVN. These results indicated that asprosin in the PVN increased the sympathetic outflow, blood pressure, and heart rate via cAMP–PKA signaling-mediated NADPH oxidase activation and the subsequent superoxide production.

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus

“…The expression of ROS and the level of inflammatory cytokines within PVN increased significantly in hypertension. PVN infusion with superoxide scavenger tempol and NADPH oxidase inhibitor can attenuate hypertension [ 42 , 43 ]. Our results showed that luteolin obviously decreased NAD(P)H-dependent ROS production in PVN, suggesting that luteolin can play its antioxidant role in the central nervous system.…”

Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects

“…This signaling pathway may also be implicated in the cardiovascular-related effects of asprosin. Recently, high expression levels of asprosin mRNA and protein were detected in another hypothalamic nucleus known as paraventricular nucleus (PVN) ( 26 ). Interestingly, asprosin induced the sympathetic outflow in the PVN via activation of the cAMP–PKA signaling pathway mediated by NADPH oxidase activation and subsequent reactive oxygen species (ROS) production ( Figure 1 ) ( 26 ).…”

“…Recently, high expression levels of asprosin mRNA and protein were detected in another hypothalamic nucleus known as paraventricular nucleus (PVN) ( 26 ). Interestingly, asprosin induced the sympathetic outflow in the PVN via activation of the cAMP–PKA signaling pathway mediated by NADPH oxidase activation and subsequent reactive oxygen species (ROS) production ( Figure 1 ) ( 26 ). Microinjection of asprosin protein in PVN of adult Sprague-Dawley rats caused increasing levels of heart rate, mean arterial pressure, and renal sympathetic nerve activity in a dose-dependent manner ( 26 ).…”

“…Interestingly, asprosin induced the sympathetic outflow in the PVN via activation of the cAMP–PKA signaling pathway mediated by NADPH oxidase activation and subsequent reactive oxygen species (ROS) production ( Figure 1 ) ( 26 ). Microinjection of asprosin protein in PVN of adult Sprague-Dawley rats caused increasing levels of heart rate, mean arterial pressure, and renal sympathetic nerve activity in a dose-dependent manner ( 26 ). However, neutralization of the endogenous asprosin with a specific antibody eliminated the previous asprosin-dependent actions ( 26 ).…”

“…Microinjection of asprosin protein in PVN of adult Sprague-Dawley rats caused increasing levels of heart rate, mean arterial pressure, and renal sympathetic nerve activity in a dose-dependent manner ( 26 ). However, neutralization of the endogenous asprosin with a specific antibody eliminated the previous asprosin-dependent actions ( 26 ).…”