Journal article
Hyperglycemia-induced cardiomyocyte death is mediated by lysosomal membrane injury and aberrant expression of cathepsin D
Biochemical and biophysical research communications, Vol.523(1), pp.239-245
02/26/2020
DOI: 10.1016/j.bbrc.2019.12.051
PMCID: PMC6941191
PMID: 31862139
Abstract
Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Previous studies have shown an association between lysosomal dysfunction and diabetic heart injury. The present study examined if mimicking hyperglycemia in cultured cardiomyocytes could induce lysosomal membrane permeabilization (LMP), leading to the release of lysosome enzymes and subsequent cell death. High glucose (HG) reduced the number of lysosomes with acidic pH as shown by a fluorescent pH indicator. Also, HG induced lysosomal membrane injury as shown by an accumulation of Galectin3-RFP puncta, which was accompanied by the leakage of cathepsin D (CTSD), an aspartic protease that normally resides within the lysosomal lumen. Furthermore, CTSD expression was increased in HG-cultured cardiomyocytes and in the hearts of 2 mouse models of type 1 diabetes. Either CTSD knockdown with siRNA or inhibition of CTSD activity by pepstatin A markedly diminished HG-induced cardiomyocyte death, while CTSD overexpression exaggerated HG-induced cell death. Together, these results suggested that HG increased CTSD expression, induced LMP and triggered CTSD release from the lysosomes, which collectively contributed to HG-induced cardiomyocyte injury.
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•Hyperglycemia induced Cathepsin D in mouse heart and in cultured cardiomyocytes.•High glucose increased lysosomal membrane permeability in cultured cardiomyocytes.•High glucose triggered Cathepsin D leakage from the lysosome in cardiomyocytes.•Cathepsin D knockdown or inhibition reduced high glucose cardiotoxicity.•Cathepsin D overexpression exaggerated high glucose-induced cardiomyocyte death.
Details
- Title: Subtitle
- Hyperglycemia-induced cardiomyocyte death is mediated by lysosomal membrane injury and aberrant expression of cathepsin D
- Creators
- Satoru Kobayashi - Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York, 11568, USAFengyi Zhao - First Affiliated Hospital of Xi'an Jiaotong UniversityTamayo Kobayashi - Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York, 11568, USAMariko Hagiwara - Roy J. and Lucille A. Carver College of MedicineAmanda Kaminaris - Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York, 11568, USACairong Li - Hubei University of Science and TechnologyFei Cai - Hubei University of Science and TechnologyYuan Huang - Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York, 11568, USAQiangrong Liang - Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York, 11568, USA
- Resource Type
- Journal article
- Publication Details
- Biochemical and biophysical research communications, Vol.523(1), pp.239-245
- DOI
- 10.1016/j.bbrc.2019.12.051
- PMID
- 31862139
- PMCID
- PMC6941191
- NLM abbreviation
- Biochem Biophys Res Commun
- ISSN
- 0006-291X
- eISSN
- 1090-2104
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association, award: 15SDG25080077; DOI: 10.13039/100000002, name: National Institutes of Health, award: 1R15HL137130-01A1
- Language
- English
- Date published
- 02/26/2020
- Academic Unit
- General Internal Medicine; Internal Medicine
- Record Identifier
- 9984359832302771
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