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棕色脂肪组织来源的成纤维细胞生长因子 21 介导右美托咪定在心肌缺血/再灌注损伤中的心脏保护作用。

Brown adipose tissue-derived FGF21 mediates the cardioprotection of dexmedetomidine in myocardial ischemia/reperfusion injury.

机构信息

Department of Anesthesiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, 214125, People's Republic of China.

Laboratory of Metabolic and Inflammatory Diseases, Wuxi School of Medicine, Jiangnan University, No.1800, Lihu Road, Wuxi, 214125, People's Republic of China.

出版信息

Sci Rep. 2024 Aug 7;14(1):18292. doi: 10.1038/s41598-024-69356-w.

DOI:10.1038/s41598-024-69356-w
PMID:39112671
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11306229/
Abstract

Brown adipose tissue (BAT) plays a critical role in regulating cardiovascular homeostasis through the secretion of adipokines, such as fibroblast growth factor 21 (FGF21). Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist with a protection against myocardial ischemia/reperfusion injury (MI/RI). It remains largely unknown whether or not BAT-derived FGF21 is involved in DEX-induced cardioprotection in the context of MI/RI. Herein, we demonstrated that DEX alleviated MI/RI and improved heart function through promoting the release of FGF21 from interscapular BAT (iBAT). Surgical iBAT depletion or supplementation with a FGF21 neutralizing antibody attenuated the beneficial effects of DEX. AMPK/PGC1α signaling-induced fibroblast growth factor 21 (FGF21) release in brown adipocytes is required for DEX-mediated cardioprotection since blockade of the AMPK/PGC1α axis weakened the salutary effects of DEX. Co-culture experiments showed that DEX-induced FGF21 from brown adipocytes increased the resistance of cardiomyocytes to hypoxia/reoxygenation (H/R) injury via modulating the Keap1/Nrf2 pathway. Our results provided robust evidence that the BAT-cardiomyocyte interaction is required for DEX cardioprotection, and revealed an endocrine role of BAT in DEX-mediating protection of hearts against MIRI.

摘要

棕色脂肪组织 (BAT) 通过分泌脂联素等细胞因子，如成纤维细胞生长因子 21 (FGF21)，在调节心血管稳态方面发挥着关键作用。右美托咪定 (DEX) 是一种选择性α2-肾上腺素能受体激动剂，具有心肌缺血/再灌注损伤 (MI/RI) 的保护作用。目前尚不清楚 BAT 衍生的 FGF21 是否参与 DEX 诱导的 MI/RI 中的心脏保护作用。在此，我们证明 DEX 通过促进肩胛间 BAT (iBAT) 中 FGF21 的释放来减轻 MI/RI 并改善心脏功能。手术性 iBAT 耗竭或用 FGF21 中和抗体进行补充会减弱 DEX 的有益作用。AMPK/PGC1α 信号诱导的成纤维细胞生长因子 21 (FGF21) 在棕色脂肪细胞中的释放是 DEX 介导的心脏保护所必需的，因为 AMPK/PGC1α 轴的阻断削弱了 DEX 的有益作用。共培养实验表明，DEX 诱导的棕色脂肪细胞产生的 FGF21 通过调节 Keap1/Nrf2 通路增加了心肌细胞对缺氧/复氧 (H/R) 损伤的抵抗力。我们的研究结果为 BAT-心肌细胞相互作用是 DEX 心脏保护所必需的提供了有力证据，并揭示了 BAT 在 DEX 介导的心脏对抗 MIRI 保护中的内分泌作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e66/11306229/c3c2eca05d7f/41598_2024_69356_Fig7_HTML.jpg
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