PMID- 35584327
OWN - NLM
STAT- MEDLINE
DCOM- 20221111
LR  - 20231102
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 323
IP  - 5
DP  - 2022 Nov 1
TI  - Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death.
PG  - C1555-C1575
LID - 10.1152/ajpcell.00369.2021 [doi]
AB  - Chaperone-mediated autophagy (CMA) is a chaperone-dependent process of selective 
      cytosolic protein turnover that targets specific proteins to lysosomes for 
      degradation. Enhancing protein degradation mechanisms has been shown to be 
      beneficial in multiple models of cardiac disease, including myocardial infarction 
      (MI) and ischemia-reperfusion (I/R) injury. However, the causal role of CMA in 
      cardiomyocyte injury and death is largely unknown. Hypoxia is an important 
      contributor to both MI and I/R damage, which are major, precedent causes of heart 
      failure. Upregulating CMA was hypothesized to protect against hypoxia-induced 
      cardiomyocyte death. Lysosome-associated membrane protein 2a (Lamp2a) 
      overexpression and knockdown were used to causally study CMA's role in 
      hypoxically stressed cardiomyocytes. LAMP2a protein levels were used as both a 
      primary indicator and driver of CMA function. Hypoxic stress was stimulated by 
      CoCl(2) treatment, which increased LAMP2a protein levels (+1.4-fold) and induced 
      cardiomyocyte apoptosis (+3.2-4.0-fold). Lamp2a siRNA knockdown (-3.2-fold) of 
      control cardiomyocytes increased apoptosis (+1.8-fold) suggesting that loss of 
      CMA is detrimental for cardiomyocyte survival. However, there was neither an 
      additive nor a synergistic effect on cell death when Lamp2a-silenced cells were 
      treated with CoCl(2). Conversely, Lamp2a overexpression (+3.0-fold) successfully 
      reduced hypoxia-induced apoptosis by  approximately 50%. LAMP2a was also significantly 
      increased (+1.7-fold) in ischemic heart failure patient samples, similar to 
      hypoxically stressed cardiomyocytes. The failing ischemic hearts may have had 
      insufficient CMA activation. To our knowledge, this study for the first time 
      establishes a protective role for CMA (via Lamp2a overexpression) against 
      hypoxia-induced cardiomyocyte loss and reveals the intriguing possibility that 
      CMA activation may offer a cardioprotective treatment for ischemic heart disease.
FAU - Ghosh, Rajeshwary
AU  - Ghosh R
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine, University of 
      South Dakota, Vermillion, South Dakota.
AD  - Department of Nutrition and Integrative Physiology Program in Molecular Medicine, 
      University of Utah, Salt Lake City, Utah.
FAU - Gillaspie, Jennifer Jason
AU  - Gillaspie JJ
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine, University of 
      South Dakota, Vermillion, South Dakota.
FAU - Campbell, Kenneth S
AU  - Campbell KS
AUID- ORCID: 0000-0001-5615-5958
AD  - Department of Physiology, College of Medicine, University of Kentucky, Lexington, 
      Kentucky.
FAU - Symons, J David
AU  - Symons JD
AD  - Department of Nutrition and Integrative Physiology Program in Molecular Medicine, 
      University of Utah, Salt Lake City, Utah.
FAU - Boudina, Sihem
AU  - Boudina S
AD  - Department of Nutrition and Integrative Physiology Program in Molecular Medicine, 
      University of Utah, Salt Lake City, Utah.
FAU - Pattison, James Scott
AU  - Pattison JS
AUID- ORCID: 0000-0003-2920-1909
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine, University of 
      South Dakota, Vermillion, South Dakota.
LA  - eng
GR  - R01 HL149870/HL/NHLBI NIH HHS/United States
GR  - U54 GM115458/GM/NIGMS NIH HHS/United States
GR  - R01 HL149164/HL/NHLBI NIH HHS/United States
GR  - R01 HL141540/HL/NHLBI NIH HHS/United States
GR  - R01 HL148785/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220518
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - EVS87XF13W (cobaltous chloride)
SB  - IM
MH  - Humans
MH  - Lysosomal-Associated Membrane Protein 2/genetics/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - *Chaperone-Mediated Autophagy
MH  - Autophagy/genetics
MH  - Lysosomes/metabolism
MH  - Hypoxia/metabolism
MH  - Apoptosis
MH  - *Heart Failure/metabolism
PMC - PMC9829466
OTO - NOTNLM
OT  - cardiomyocytes
OT  - cell death
OT  - chaperone-mediated autophagy
OT  - hypoxia
OT  - ischemic heart failure
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2022/05/19 06:00
MHDA- 2022/11/15 06:00
PMCR- 2023/11/01
CRDT- 2022/05/18 15:53
PHST- 2022/05/19 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
PHST- 2022/05/18 15:53 [entrez]
PHST- 2023/11/01 00:00 [pmc-release]
AID - C-00369-2021 [pii]
AID - 10.1152/ajpcell.00369.2021 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2022 Nov 1;323(5):C1555-C1575. doi: 
      10.1152/ajpcell.00369.2021. Epub 2022 May 18.