Resveratrol reduces RVLM neuron activity via activating the AMPK/Sirt3 pathway in stress-induced hypertension

• Published in: The Journal of biological chemistry Vol. 301; no. 4; p. 108394
• Main Authors: Wang, Lin-Ping, Liu, Tian-Feng, Dai, Teng-Teng, Deng, Xin, Tong, Lei, Zeng, Qiang-Cheng, He, Qing, Ren, Zhang-Yan, Zhang, Hai-Li, Liu, Hai-Sheng, Li, Yan-Fang, Li, Wen-Zhi, Zhang, Shuai, Du, Dong-Shu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2025; American Society for Biochemistry and Molecular Biology
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Antioxidants - pharmacology; apoptosis; Apoptosis - drug effects; ferroptosis; Hypertension - drug therapy; Hypertension - etiology; Hypertension - metabolism; Hypertension - pathology; Male; Medulla Oblongata - drug effects; Medulla Oblongata - metabolism; Medulla Oblongata - pathology; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial oxidative stress; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; reactive oxygen species; Resveratrol - pharmacology; RVLM; Signal Transduction - drug effects; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Sirtuins; DHE; Cyt-cyto C; ferroptosis; mitochondrial oxidative stress; apoptosis; HR; MDA; BP; Com.C; RSNA; reactive oxygen species; CCK-8; cDNA; RVLM; DCF; qRT-PCR; SOD; MMP; SIH; RSV; TH; AAV; CAT; NE; ROS; TEM
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2025.108394

Neuronal hyperexcitability in the rostral ventrolateral medulla (RVLM), driven by oxidative stress, plays a crucial role in stress-induced hypertension (SIH). While resveratrol (RSV) is known for its antioxidant properties, its effects on RVLM neurons in SIH remain unclear. We investigated this using an SIH rat model exposed to electric foot shocks and noise stimulation for 15 days. Analysis of RVLM tissue revealed increased mitochondrial damage, oxidative stress, apoptosis, and dysregulated ferroptosis in SIH rats. RSV microinjection into the RVLM reduced blood pressure, sympathetic vascular tone, and neuronal excitability. Both in vivo and in vitro studies showed that RSV treatment alleviated mitochondrial oxidative stress, apoptosis, and ferroptosis through AMPK activation and subsequent Sirt3 upregulation. These therapeutic effects were blocked by either AMPK inhibition or Sirt3 knockdown. Our findings demonstrate that RSV attenuates SIH by activating the AMPK/Sirt3 pathway, thereby reducing RVLM oxidative stress and cell death.