Lactate Contributes to Remote Ischemic Preconditioning-Mediated Protection Against Myocardial Ischemia Reperfusion Injury by Facilitating Autophagy via the AMP-Activated Protein Kinase-Mammalian Target of Rapamycin-Transcription Factor EB-Connexin 43 Axis.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0370502 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-2191 (Electronic) Linking ISSN: 00029440 NLM ISO Abbreviation: Am J Pathol Subsets: MEDLINE
    • Publication Information:
      Publication: 2011-: New York : Elsevier
      Original Publication: Philadelphia [etc.] American Assn. of Pathologists [etc.]
    • Subject Terms:
      AMP-Activated Protein Kinases*/metabolism ; Autophagy*/drug effects ; Autophagy*/physiology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/metabolism ; Connexin 43*/metabolism ; Connexin 43*/genetics ; Myocardial Reperfusion Injury*/prevention & control ; Myocardial Reperfusion Injury*/metabolism ; Myocardial Reperfusion Injury*/pathology ; TOR Serine-Threonine Kinases*/metabolism; Animals ; Male ; Rats ; Ischemic Preconditioning/methods ; Lactic Acid/metabolism ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Signal Transduction/drug effects
    • Abstract:
      Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.
      Competing Interests: Disclosure Statement None declared.
      (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
    • Accession Number:
      EC 2.7.11.31 (AMP-Activated Protein Kinases)
      0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
      0 (Connexin 43)
      33X04XA5AT (Lactic Acid)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
      0 (TFEB protein, rat)
      EC 2.7.1.1 (mTOR protein, rat)
    • Publication Date:
      Date Created: 20240728 Date Completed: 20240925 Latest Revision: 20241002
    • Publication Date:
      20241002
    • Accession Number:
      10.1016/j.ajpath.2024.07.005
    • Accession Number:
      39069170