Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension

Abstract

Recent studies have reported that the activation of AMP-activated protein kinase (AMPK) suppressed oxidative stress. The aim of this study was to examine whether the activation of AMPK in the brain decreased Rac1-induced ROS generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The inhibition of ROS by treatment with an AMPK activator (oral resveratrol, 10 mg/kg/day) for 1 week decreased the BP and increased the NO production in the rostral ventrolateral medulla (RVLM) of fructose-fed rats but not in control Wistar-Kyoto (WKY) rats. In addition, resveratrol treatment abolished the Rac1-induced increases in the activity of the NADPH oxidase subunits p22-phox and reduced the activity of SOD2, while treatment with an AMPK inhibitor (compound C, 40 μM/day) had the opposite effect, in the fructose-fed rats. Interestingly, the activation of AMPK abolished Rac1 activation and decreased BP by inducing the activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and nNOS phosphorylation in the fructose-fed rats. We conclude that the activation of AMPK decreased BP, abolished ROS generation, and enhanced ERK1/2-RSK-nNOS pathway activity by negatively regulating Racl-induced NADPH oxidase levels in the RVLM during oxidative stress–associated hypertension.

Maternal protein restriction induced‐hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata

“…26 SOD2 is the gatekeeper that regulates the (physiological) conversion of superoxide anion to H 2 O 2 and clinical and experimental evidences have demonstrated that mRNA expression of SOD2 is down regulated in pulmonary arterial hypertension [30][31][32][33] and that SOD2 protein expression levels are also down regulated in the RVLM of fructose-induced hypertension rat model. 34 In our study, the expression of SOD2 mRNA decreased in the medulla of rats exposed to perinatal protein restriction. This result is in keeping with the hypertension models described above, suggesting that reduced SOD2 in medulla is linked to the hypertensive condition.…”

“…At transcript levels, ROS have been reported as key molecular species altering gene transcription of antioxidant enzymes . SOD2 is the gatekeeper that regulates the (physiological) conversion of superoxide anion to H 2 O 2 and clinical and experimental evidences have demonstrated that mRNA expression of SOD2 is down regulated in pulmonary arterial hypertension and that SOD2 protein expression levels are also down regulated in the RVLM of fructose‐induced hypertension rat model …”

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

“…In addition, quercetin and resveratrol, which are similar to naringenin, exert stronger activities to induce AMPK and ATF3 activation. Therefore, our findings may indicate a common feature of naringenin and other polyphenol analogues, which exert anti-inflammatory activities by activating the AMPK-ATF3 signalling pathway3031.…”

Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCγ/Rac1 pathway in salt-induced hypertension

“…MDA, SOD, GSH and NAD(P)H oxidase activity in PVN were quantified using commercially available rat ELISA kits (Invitrogen Corporation, CA, USA) according to the manufacturer’s instructions29303132. NE in plasma were quantified using commercially available rat ELISA kits (Invitrogen Corporation, CA, USA) according to the manufacturer’s instructions6.…”