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AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics

Jingxia Du1, Hongchao Li2, Jingjing Song1

  • 1Pharmacy Department, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, China.

Frontiers in Pharmacology
|July 21, 2022
PubMed

Insights

Activation of Adenosine monophosphate-activated protein kinase (AMPK) protects against myocardial ischemia/reperfusion injury (MIRI) by inhibiting mitochondrial fission. This involves regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics, reducing inflammation, and improving cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Medicine
  • Cellular Signaling

Background:

  • Mitochondrial dysfunction is a key factor in myocardial ischemia/reperfusion injury (MIRI).
  • The precise mechanisms of mitochondrial dynamics disruption in MIRI are not fully understood.
  • Adenosine monophosphate-activated protein kinase (AMPK) is a potential therapeutic target for MIRI.

Purpose of the Study:

  • To investigate if AMPK activation alleviates MIRI by modulating Drp1-mediated mitochondrial dynamics.
  • To elucidate the role of Drp1 in AMPK-induced protection against MIRI.

Main Methods:

  • Isolated mouse hearts and H9C2 cells were subjected to ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury.
  • Treatment with AICAR (AMPK activator) and Mdivi-1 (Drp1 inhibitor) was employed.
  • Measurements included cardiac function, infarct size, oxidative stress markers, inflammatory cytokines, and mitochondrial dynamics gene expression.

Main Results:

  • AICAR treatment improved cardiac function, reduced infarct size, and decreased arrhythmia incidence in MIRI models.
  • AICAR inhibited Drp1 phosphorylation at Ser 616, reduced fission gene expression, and decreased inflammatory cytokines.
  • Mdivi-1 mimicked AICAR's protective effects, suggesting Drp1 inhibition is crucial for AMPK-mediated cardioprotection.

Conclusions:

  • AMPK activation confers significant protection against MIRI.
  • This protection is mediated through the inhibition of Drp1-dependent mitochondrial fission.
  • Targeting AMPK and Drp1 represents a promising therapeutic strategy for MIRI.
Keywords:
AMPKDRP1ROSinflammatory factorsmitochondrial dynamicsmyocardial ischemia/reperfusion injury

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