Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.
Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure.
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DOI：
10.1016/j.jacbts.2022.06.003
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发表时间：
2022-12
影响因子：
9.7
通讯作者：
Mann, Douglas L.
中科院分区：
文献类型：
--
作者：
Evans, Sarah;Ma, Xiucui;Wang, Xiqiang;Chen, Yana;Zhao, Chen;Weinheimer, Carla J.;Kovacs, Attila;Finck, Brian;Diwan, Abhinav;Mann, Douglas L.
逆转左心室重构的生物学驱动因素还不清楚。经主动脉收缩诱导的血液动力学压力超负荷叠加在小鼠中的急性LAD结扎上导致雷帕霉素活化的哺乳动物靶标增加、自噬通量降低、线粒体自噬增加、线粒体氧化能力降低以及心肌细胞中受损蛋白质和细胞器的积累。通过去除经主动脉收缩的血液动力学卸载导致逆转LV重构，雷帕霉素活化的哺乳动物靶标增加，自噬通量的恢复和线粒体氧化能力的正常化，但受损蛋白质和细胞器的不完全去除在已经经历血液动力学卸载的小鼠中用AAV 9-CMV-转录因子EB增强自噬通量导致与用AAV 9-CMV-GFP处理的对照小鼠相比更有利的逆转LV重塑，而用AAV 9-CMV-转录因子EB处理未经历血液动力学卸载的小鼠导致增加的致死率。负责逆转左心室（LV）重塑的关键生物学“驱动因素”尚未得到很好的理解。为了理解自噬-溶酶体途径在逆转LV重构中的作用，我们使用了可逆性心力衰竭的病理生理学相关的鼠模型，其中通过经主动脉缩窄叠加在急性冠状动脉（心肌梗死）结扎上的压力超负荷导致心力衰竭表型，其通过血流动力学卸载是可逆的。在这里，我们表明，经主动脉缩窄+心肌梗死导致通过自噬-溶酶体途径的流量减少，心肌细胞中受损蛋白和细胞器积聚，而血流动力学卸载与自噬流量恢复到正常水平有关，心肌细胞中受损蛋白和细胞器的不完全清除和逆转LV重塑，表明流量的恢复不足以完全恢复心肌蛋白质稳态。用腺相关病毒9-转录因子EB增强自噬通量导致经历血液动力学卸载的小鼠中更有利的逆转LV重构，而在没有经历血液动力学卸载的小鼠中过度表达转录因子EB导致死亡率增加，这表明增强自噬通量的治疗结果将取决于正在研究的通量的条件。
The biological drivers of reverse LV remodeling are not well understood. Transaortic constriction induced hemodynamic pressure overload superimposed on acute LAD ligation in mice resulted in increased mammalian target of rapamycin activation, decreased autophagic flux, increased mitophagy, decreased mitochondrial oxidative capacity, and accumulation of damaged proteins and organelles in cardiac myocytes Hemodynamic unloading by removing the transaortic constriction leads to reverse LV remodeling, increased mammalian target of rapamycin activation, restoration of autophagic flux, and normalization of mitochondrial oxidative capacity, but incomplete removal of damaged proteins and organelles Enhancing autophagic flux with AAV9- CMV-transcription factor EB in mice that have undergone hemodynamic unloading resulted in more favorable reverse LV remodeling compared with control mice treated with AAV9-CMV-GFP, whereas treating mice that have not undergone hemodynamic unloading with AAV9-CMV-transcription factor EB leads to increased lethality. The key biological “drivers” that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9–transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied.
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影响因子：
8
作者：
Evans, Sarah;Tzeng, Huei-Ping;Mann, Douglas L.
通讯作者：
Mann, Douglas L.
DOI：
10.1016/j.jacbts.2021.12.002
发表时间：
2022-03
期刊：
JACC. Basic to translational science
影响因子：
--
作者：
Ma X;Rawnsley DR;Kovacs A;Islam M;Murphy JT;Zhao C;Kumari M;Foroughi L;Liu H;Qi K;Diwan A;Hyrc K;Evans S;Satoh T;French BA;Margulies KB;Javaheri A;Razani B;Mann DL;Mani K;Diwan A
通讯作者：
Diwan A
影响因子：
3.8
作者：
Ji CH;Kwon YT
通讯作者：
Kwon YT
影响因子：
8
作者：
Chambers, Kari T.;Cooper, Michael A.;Finck, Brian N.
通讯作者：
Finck, Brian N.
影响因子：
4.4
作者：
Lee, Hye-Mi;Shin, Dong-Min;Jo, Eun-Kyeong
通讯作者：
Jo, Eun-Kyeong