Cui Lin, Zhao Li-Ping, Ye Jing-Ying, Yang Lei, Huang Yao, Jiang Xu-Pin, Zhang Qiong, Jia Jie-Zhi, Zhang Dong-Xia, Huang Yuesheng
Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Friendship Plastic Surgery Hospital, Nanjing Medical University, Nanjing, China.
Front Cell Dev Biol. 2020 Feb 7;8:31. doi: 10.3389/fcell.2020.00031. eCollection 2020.
Lysosomal membrane permeabilization (LMP) has recently been recognized as an important cell death pathway in various cell types. However, studies regarding the correlation between LMP and cardiomyocyte death are scarce. Lysosomal membrane-associated protein 2 (Lamp2) is an important component of lysosomal membranes and is involved in both autophagy and LMP. In the present study, we found that the protein content of Lamp2 gradually decreased in response to oxygen, glucose and serum deprivation (OGD) treatment . To further elucidate its role in ischemic cardiomyocytes, particularly with respect to autophagy and LMP, we infected cardiomyocytes with adenovirus carrying full-length Lamp2 to restore its protein level in cells. We found that OGD treatment resulted in the occurrence of LMP and a decline in the viability of cardiomyocytes, which were remarkably reversed by Lamp2 restoration. Exogenous expression of Lamp2 also significantly alleviated the autophagic flux blockade induced by OGD treatment by promoting the trafficking of cathepsin B (Cat B) and cathepsin D (Cat D). Through drug intervention and gene regulation to alleviate and exacerbate autophagic flux blockade respectively, we found that impaired autophagic flux in response to ischemic injury contributed to the occurrence of LMP in cardiomyocytes. In conclusion, our present data suggest that Lamp2 overexpression can improve autophagic flux blockade probably by promoting the trafficking of cathepsins and consequently conferring cardiomyocyte resistance against lysosomal cell death (LCD) that is induced by ischemic injury. These results may indicate a new therapeutic target for ischemic heart damage.
溶酶体膜通透性改变（LMP）最近被认为是多种细胞类型中一种重要的细胞死亡途径。然而，关于LMP与心肌细胞死亡之间相关性的研究却很少。溶酶体膜相关蛋白2（Lamp2）是溶酶体膜的重要组成部分，参与自噬和LMP过程。在本研究中，我们发现，在氧糖剥夺（OGD）处理后，Lamp2的蛋白含量逐渐降低。为了进一步阐明其在缺血心肌细胞中的作用，特别是在自噬和LMP方面的作用，我们用携带全长Lamp2的腺病毒感染心肌细胞，以恢复其在细胞中的蛋白水平。我们发现，OGD处理导致LMP的发生和心肌细胞活力下降，而Lamp2的恢复可显著逆转这些变化。Lamp2的外源性表达还通过促进组织蛋白酶B（Cat B）和组织蛋白酶D（Cat D）的转运，显著减轻了OGD处理诱导的自噬流阻断。通过药物干预和基因调控分别减轻和加剧自噬流阻断，我们发现，缺血损伤后自噬流受损促成了心肌细胞中LMP的发生。总之，我们目前的数据表明，Lamp2过表达可能通过促进组织蛋白酶的转运来改善自噬流阻断，从而赋予心肌细胞抵抗缺血性损伤诱导的溶酶体细胞死亡（LCD）的能力。这些结果可能为缺血性心脏损伤指明一个新的治疗靶点。
