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Cited by 62Autophagy in Disease and TherapyCell death mechanisms and regulationCardiac Ischemia and Reperfusion

The lysosomal membrane protein Lamp2 alleviates lysosomal cell death by promoting autophagic flux in ischemic cardiomyocytes

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Cui·2020·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2020.00031PMC PMC7019187
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Abstract

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 in vitro. 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.

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  • A decrease in LAMP2 levels causes a lack of lysosomal trafficking and decrease in autophagic flux.

    “It is known that a decrease in LAMP2 levels causes a lack of lysosomal trafficking and decrease in autophagic flux (Cui et al., 2020).”

    From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Cui et al., 2020

    The Discussion reports that Lamp2 knockdown blocked autophagic flux, and the Results show that Lamp2 restoration improved trafficking of the lysosomal cathepsins Cat B and Cat D. The paper does not establish that decreased Lamp2 causes a complete lack of lysosomal trafficking generally; its trafficking finding concerns those cathepsins in ischemic cardiomyocytes. (LLM, conf=0.83)

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Sorted by citations

Authors
Cui
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2020-02-07
Volume
8
Pages
31-31
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2020.00031
PMC
PMC7019187
OpenAlex
W3005374439
Cited by
62
References
3
Citations by year
2026: 3 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 6 · 2021: 14 · 2020: 3
FWCI
6.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81430042)
  • Army Medical University
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
LAMP2, lysosomal membrane permeabilization, lysosomal cell death, autophagic flux, cathepsin B, cathepsin D, cardiomyocyte viability, therapeutic target

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