Resveratrol regulates blood pressure by enhancing AMPK signaling to downregulate a Rac1-derived NADPH oxidase in the central nervous system

Abstract

Resveratrol is a polyphenol with pleiotropic effects against oxidative damage that has been widely implicated in lowering hypertension risk. The purpose of this study was to determine whether improve nitric oxide (NO) release in the brain, either through the activation of AMP-activated protein kinase (AMPK) or reduced Ras-related C3 botulinum toxin substrate 1 (Rac1)-induced reactive oxygen species (ROS) generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The rats were fed with 10% fructose or Crestor (rosuvastatin; 1.5 mg·kg·day) and resveratrol (10 mg·kg·day) treatment for 1 wk, then the systolic blood pressure of the rats was measured by tail-cuff method. Endogenous in vivo superoxide radical production in the nucleus tractus solitarii (NTS) was determined with dihydroethidium. Immunoblotting analyses were used to quantify protein expression levels. Oral resveratrol treatment for 1 wk decreased BP and increased NO production in the NTS of fructose-fed rats but not in the control Wistar-Kyoto rats. The effect of Crestor is opposite that of resveratrol. Fructose induced hypertension by inactivating AMPK, which in turn enhanced the generation of ROS and reduced manganese superoxide dismutase by increasing the activity of Rac1-induced NADPH oxidase, abolishing the activity of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and neuronal nitric oxide synthase (nNOS) phosphorylation signaling pathway in the brain. However, resveratrol had the opposite effect in the fructose-fed rats. Overall, we show that the resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-RSK-nNOS pathway by activating AMPK to downregulate Rac1-induced NADPH oxidase levels in the NTS during oxidative stress-associated hypertension. NEW & NOTEWORTHY 1) Evidence showed that the Ras-related C3 botulinum toxin substrate 1 (Rac1) augmented by Crestor (rosuvastatin) did not result in a significant change in blood pressure (BP) in fructose-induced hypertension. 2) Fructose induced hypertension by inactivating AMP-activated protein kinase (AMPK), which in turn enhanced the generation of reactive oxygen species (ROS) and reduced manganese superoxide dismutase in the brain. 3) Resveratrol decreased BP better than Crestor, abolished ROS generation, and enhanced the ERK1/2-ribosomal protein S6 kinase-neuronal nitric oxide synthase pathway by activating AMPK to negatively regulate Rac1-induced NADPH oxidase levels in the nucleus tractus solitarii during oxidative stress-associated hypertension.

Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer’s Disease

“…Oxidative stress can be defined as increased bioactivity of ROS relative to antioxidant defences [37]. In accordance with our present findings, our previous studies demonstrated that resveratrol decreases BP better than rosuvastatin, abolishes ROS generation, and enhances activity of the ERK1/2-RSK-nNOS pathway by activating AMPK to negatively regulate Racl-induced NADPH oxidase levels in the NTS during oxidative stress-associated hypertension [38].…”

Resveratrol attenuates oxidative stress during experimental periodontitis in rats exposed to cigarette smoke inhalation

“…In this regard, a recent study demonstrated reduced activation of NADPH oxidase/ROS/NF‐κB pathways in human fibroblast‐like synoviocytes after resveratrol treatment, leading to the suppression of particulate matter air pollution‐induced COX‐2 expression and PGE2 release . Other studies have demonstrated the regulatory effect of resveratrol on the expression of NADPH oxidase . Therefore, the observed reduction in NADPH oxidase levels demonstrated with resveratrol is consistent with reduced inflammatory bone loss caused by CIS.…”

“…56 Other studies have demonstrated the regulatory effect of resveratrol on the expression of NADPH oxidase. [57][58][59][60] Therefore, the observed reduction in NADPH oxidase levels demonstrated with resveratrol is consistent with reduced inflammatory bone loss caused by CIS.…”

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

“…Collectively, these pieces of evidence show that the antioxidant effect of rosiglitazone and AICAR is mediated by AMPK-dependent inhibition of NADPH oxidase [216]. is was furthered by different other studies using resveratrol [194,217,218]. us, AMPK-dependent activation of NADPH oxidase and consequent reduction of ROS generation play an immense role in the antioxidant effect of AMPK activators.…”