Beclin-1单倍体缺陷可通过抑制替代性有丝分裂改善高脂饮食诱发的心肌损伤。

IF 5.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants & redox signaling Pub Date : 2024-06-01 Epub Date: 2024-03-05 DOI:10.1089/ars.2023.0399
Xiaofang Zeng, Jing Sun, Famei Li, Liming Peng, Chenglong Zhang, Xiaowei Jiang, Lihuang Zha, Anandharajan Rathinasabapathy, Jun Ren, Zaixin Yu, Lin Wang, Xiangwei Liu
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引用次数: 0

摘要

目的:线粒体平衡对维持氧化还原平衡至关重要。除了典型的自噬,依赖 Rab9 的替代性有丝分裂也是代谢性心肌病的一个重要机制。结果:24 周高脂肪膳食损害了 WT 小鼠的葡萄糖耐量和心肌细胞收缩能力,而 Beclin 1+/- 小鼠的这两种情况都得到了缓解。Beclin 1单倍体缺陷对传统的自噬介质(ATG5、LC3II/LC3I)几乎没有影响,但却进一步上调了Rab9的表达,Rab9是替代性自噬的标志物,是对高密度脂蛋白胆固醇挑战的反应。此外,抑制替代性自噬或Beclin 1单倍体缺陷均可消除棕榈酸诱导的心肌细胞收缩异常。在体外,棕榈酸过度激活了有丝分裂,导致 H9C2 细胞中线粒体含量减少。这些畸变在缺乏替代自噬功能的细胞中得到缓解,但在缺乏传统自噬功能的细胞中没有缓解。从机理上讲,HFD 促进了 ROS 的产生,激活了依赖 Rab9 的替代性自噬,并抑制了线粒体的生物合成。Beclin 1+/- 挽救了 HFD 诱导的 ROS 溢出和线粒体生物合成障碍,并阻止了 Rab9 从细胞质向线粒体的转运,从而抑制了 Rab9 介导的有丝分裂过度激活:该研究首次表明,长期替代性有丝分裂会加剧慢性高氟酸血症诱发的心功能不全,并支持Beclin 1单倍体缺陷在代谢性心肌病中的保护作用。这为基于靶点的药物干预提供了更多证据:结论:Beclin 1单倍体缺陷通过抑制Rab9依赖的替代性丝裂吞噬和ROS产生,同时促进线粒体的生物生成,对高密度脂蛋白胆固醇诱导的心脏功能障碍具有保护作用。调节Beclin 1的表达有望预防与高密度脂蛋白胆固醇相关的慢性心肌病。
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Beclin 1 Haploinsufficiency Ameliorates High-Fat Diet-Induced Myocardial Injury via Inhibiting Alternative Mitophagy.
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来源期刊
Antioxidants & redox signaling
Antioxidants & redox signaling 生物-内分泌学与代谢
CiteScore
14.10
自引率
1.50%
发文量
170
审稿时长
3-6 weeks
期刊介绍: Antioxidants & Redox Signaling (ARS) is the leading peer-reviewed journal dedicated to understanding the vital impact of oxygen and oxidation-reduction (redox) processes on human health and disease. The Journal explores key issues in genetic, pharmaceutical, and nutritional redox-based therapeutics. Cutting-edge research focuses on structural biology, stem cells, regenerative medicine, epigenetics, imaging, clinical outcomes, and preventive and therapeutic nutrition, among other areas. ARS has expanded to create two unique foci within one journal: ARS Discoveries and ARS Therapeutics. ARS Discoveries (24 issues) publishes the highest-caliber breakthroughs in basic and applied research. ARS Therapeutics (12 issues) is the first publication of its kind that will help enhance the entire field of redox biology by showcasing the potential of redox sciences to change health outcomes. ARS coverage includes: -ROS/RNS as messengers -Gaseous signal transducers -Hypoxia and tissue oxygenation -microRNA -Prokaryotic systems -Lessons from plant biology
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