Zhang Shutian, Huang Yijun, Han Chengzhi, Wang Fanshun, Chen Maoxiang, Yang Zhaohua, Yang Shouguo, Wang Chunsheng
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
Int Immunopharmacol. 2025 Jan 3;145:113711. doi: 10.1016/j.intimp.2024.113711. Epub 2024 Dec 7.
Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process.
Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice.
In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue.
This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂改变了心力衰竭（HF）的治疗方式，具有交感神经抑制作用，但其机制尚未完全明确。我们之前的研究发现，穹窿下器（SFO）中由环磷酸鸟苷-腺苷酸合成酶（cGAS）介导的神经炎症是交感神经兴奋的促进因素，会加重HF中的心肌重塑。本研究探讨了中枢SGLT2在HF期间诱导SFO中内皮细胞cGAS驱动的神经炎症中的作用，并评估了SGLT2抑制剂对这一过程的影响。
通过输注血管紧张素II四周诱导小鼠发生高血压性HF。通过免疫印迹和双重免疫荧光染色确定SFO中SGLT2的表达和定位。AAV9-TIE-shRNA（SGLT2）促进了SFO内皮细胞（ECs）中SGLT2的靶向敲低，随后通过免疫印迹、染色和免疫共沉淀进行分析，以研究与cGAS的相互作用、线粒体改变和促炎途径激活。测量肾交感神经活动和心率变异性以评估交感神经输出，同时评估HF小鼠的心脏功能。
在HF模型小鼠中，SFO的ECs中SGLT2水平显著升高，破坏线粒体功能并增加氧化应激。SGLT2敲低可保持线粒体完整性和功能，减少炎症，并突出了SGLT2对线粒体健康的影响。SGLT2与cGAS的相互作用阻止了其泛素化和降解，放大了神经炎症和HF进展。相反，恩格列净可抵消这些影响，表明将SGLT2-cGAS相互作用作为一种新的HF治疗途径。
本研究表明，SGLT2直接减少脑ECs中cGAS的降解，增强SFO中的神经炎症，促进交感神经兴奋和心肌重塑。强调了中枢SGLT2-cGAS相互作用在心血管疾病机制中的重要性。
