Exogenous H₂S targeting PI3K/AKT/mTOR pathway alleviates chronic intermittent hypoxia-induced myocardial damage through inhibiting oxidative stress and enhancing autophagy.

IF 2.1 4区医学 Q3 CLINICAL NEUROLOGY

Sleep and Breathing Pub Date : 2024-12-03 DOI:10.1007/s11325-024-03216-9

Xiao-Bin Zheng, Chao Wang, Ming Zhang, Bing-Qi Yao, Hai-Yan Wu, Shu-Xian Hou

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引用次数: 0

Abstract

Aims: Hydrogen sulfide (H₂S) is a novel gas signaling molecule that has been researched in several physiological and pathological conditions, indicating that strategies targeting H₂S may provide clinical benefits in diseases such as chronic cardiomyopathy. Here, we reveal the effect of H₂S on chronic intermittent hypoxia (CIH)-related myocardial damage and its mechanistic relevance to phosphoinositol-3 kinase (PI3K).

Materials: Mice were subjected to a 4-week CIH process to induce myocardial damage, which was accompanied by daily administration of NaHS (a H₂S donor) and LY294002 (an inhibitor of PI3K). Changes in heart function were evaluated via echocardiography. Histological examination was applied to assess heart tissue lesions. Myocardial apoptosis was detected by TUNEL staining and apoptosis-associated protein expression. Furthermore, the effects of NaHS on autophagy and the PI3K/AKT/mTOR pathway were investigated. Finally, the level of inflammation is also affected by related proteins.

Key findings: The CIH group presented increased myocardial dysfunction and heart tissue lesions. Echocardiography and histological analysis revealed that, compared with control mice, CIH-treated mice presented significantly more severe left ventricular remodeling and decreased myocardial contractile function. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group compared with those in the control group. The autophagy marker Beclin-1 was decreased, while p62 was elevated by CIH treatment. H₂S supplementation with NaHS significantly improved cardiac function and alleviated fibrosis, oxidative stress, and apoptosis but upregulated autophagy in CIH mice, and these effects were also observed in animals that underwent only PI3K blockade. Furthermore, PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway, the Nrf2/HO-1 pathway and proinflammatory NF-κB activity were shown to play a role in the therapeutic effect of NaHS after CIH stimulation.

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外源性H2S靶向PI3K/AKT/mTOR通路，通过抑制氧化应激和增强自噬，缓解慢性间歇性缺氧引起的心肌损伤。

目的：硫化氢（H2S）是一种新型的气体信号分子，在多种生理和病理条件下的研究表明，针对H2S的策略可能在慢性心肌病等疾病中提供临床益处。在这里，我们揭示了H2S对慢性间歇性缺氧（CIH）相关心肌损伤的影响及其与磷酸肌醇-3激酶（PI3K）的机制相关性。材料：小鼠进行为期4周的CIH过程以诱导心肌损伤，同时每天给予NaHS （H2S供体）和LY294002 （PI3K抑制剂）。通过超声心动图评估心功能的变化。应用组织学检查评估心脏组织病变。TUNEL染色检测心肌凋亡及凋亡相关蛋白表达。此外，我们还研究了NaHS对自噬和PI3K/AKT/mTOR通路的影响。最后，炎症程度也受相关蛋白的影响。主要发现：CIH组心肌功能障碍和心脏组织病变增加。超声心动图和组织学分析显示，与对照组相比，cih处理小鼠左心室重构明显加重，心肌收缩功能下降。此外，与对照组相比，CIH组细胞凋亡指数和氧化标志物明显升高。自噬标志物Beclin-1降低，p62升高。H2S补充NaHS显著改善了CIH小鼠的心功能，减轻了纤维化、氧化应激和细胞凋亡，但上调了自噬，并且在仅阻断PI3K的动物中也观察到这些作用。此外，PI3K/AKT通路介导的哺乳动物雷帕霉素靶蛋白（mTOR）通路、Nrf2/HO-1通路和促炎NF-κB活性的抑制在CIH刺激后NaHS的治疗效果中发挥了作用。

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来源期刊

Sleep and Breathing 医学-呼吸系统

CiteScore

5.20

自引率

4.00%

发文量

222

审稿时长

3-8 weeks

期刊介绍： The journal Sleep and Breathing aims to reflect the state of the art in the international science and practice of sleep medicine. The journal is based on the recognition that management of sleep disorders requires a multi-disciplinary approach and diverse perspectives. The initial focus of Sleep and Breathing is on timely and original studies that collect, intervene, or otherwise inform all clinicians and scientists in medicine, dentistry and oral surgery, otolaryngology, and epidemiology on the management of the upper airway during sleep. Furthermore, Sleep and Breathing endeavors to bring readers cutting edge information about all evolving aspects of common sleep disorders or disruptions, such as insomnia and shift work. The journal includes not only patient studies, but also studies that emphasize the principles of physiology and pathophysiology or illustrate potentially novel approaches to diagnosis and treatment. In addition, the journal features articles that describe patient-oriented and cost-benefit health outcomes research. Thus, with peer review by an international Editorial Board and prompt English-language publication, Sleep and Breathing provides rapid dissemination of clinical and clinically related scientific information. But it also does more: it is dedicated to making the most important developments in sleep disordered breathing easily accessible to clinicians who are treating sleep apnea by presenting well-chosen, well-written, and highly organized information that is useful for patient care.