Guo Yingqiang, Zhang Yu, Zhang Jinzhou, Bai Xingwan, Kang Wei, Guo Yujie, Zeng Xianming
Heart Disease Hospital, Xi'an International Medical Center Hospital, Northwest University, Xi'an, 710010, China.
Department of Cardiology, Xi'an Daxing Hospital, Xi'an, 710003, China.
Appl Biochem Biotechnol. 2025 Sep 11. doi: 10.1007/s12010-025-05359-1.
Vagus nerve stimulation (VNS) has demonstrated cardioprotective effects in a variety of cardiovascular diseases, including cardiac ischemia and reperfusion (IR) injury. However, the mechanisms responsible for these effects have not been completely understood. The present work aimed to uncover the potential mechanisms through which VNS confers protection against cardiac IR injury. Rats subjected to cardiac IR injury received electrical VNS through the right cervical vagus nerve. This intervention led to a notable reduction in cardiac dysfunction and injury, as well as decreased cardiac apoptosis, oxidative stress, and inflammation. Moreover, VNS treatment improved mitochondrial biogenesis by upregulating estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and transcriptional factor A mitochondrial (TFAM). In addition, VNS treatment not only increased the copy number of mitochondrial DNA (mtDNA) and the content of adenosine triphosphate (ATP), but also effectively reduced mitochondrial damage. VNS also upregulated the expression of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in IR-injured hearts. Inhibition of either SIRT1 or PGC-1α significantly reversed the effects of VNS on mitochondrial biogenesis and abolished its cardioprotective benefits. Notably, VNS increased the level of acetylcholine (ACh) in IR-injured hearts. Administration of atropine, a muscarinic ACh receptor (mAChR) antagonist, counteracted the effects of VNS on the SIRT1/PGC-1α pathway, mitochondrial biogenesis, and the associated cardioprotective outcomes. These findings suggest that VNS protects against cardiac I/R injury by enhancing mitochondrial biogenesis. This beneficial effect of VNS on mitochondrial biogenesis is attributed to activation of the SIRT1/PGC-1α pathway through the ACh/mAChR axis. Therefore, this research offers fresh perspectives on the mechanisms underlying the cardioprotective effects of VNS.
迷走神经刺激（VNS）已在包括心脏缺血再灌注（IR）损伤在内的多种心血管疾病中显示出心脏保护作用。然而，这些作用的机制尚未完全明确。本研究旨在揭示VNS对心脏IR损伤发挥保护作用的潜在机制。对遭受心脏IR损伤的大鼠通过右侧颈迷走神经给予电刺激。该干预导致心脏功能障碍和损伤显著减轻，同时心脏细胞凋亡、氧化应激和炎症反应减少。此外，VNS治疗通过上调雌激素相关受体α（ERRα）、核呼吸因子1（NRF-1）和线粒体转录因子A（TFAM）改善线粒体生物合成。另外，VNS治疗不仅增加了线粒体DNA（mtDNA）的拷贝数和三磷酸腺苷（ATP）的含量，还有效减少了线粒体损伤。VNS还上调了IR损伤心脏中沉默信息调节因子1（SIRT1）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的表达。抑制SIRT1或PGC-1α均可显著逆转VNS对线粒体生物合成的作用，并消除其心脏保护作用。值得注意的是，VNS增加了IR损伤心脏中的乙酰胆碱（ACh）水平。给予毒蕈碱型ACh受体（mAChR）拮抗剂阿托品可抵消VNS对SIRT1/PGC-1α通路、线粒体生物合成及相关心脏保护结果的影响。这些发现表明，VNS通过增强线粒体生物合成来保护心脏免受I/R损伤。VNS对线粒体生物合成的这种有益作用归因于通过ACh/mAChR轴激活SIRT1/PGC-1α通路。因此，本研究为VNS心脏保护作用的潜在机制提供了新的视角。
