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S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion

Yulin Li1, Boya Chen1, Xinying Yang1

  • 1Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, China (Y. Li, B.C., Z.Y., C.Z., Y.J., P.L., Y. Liu, Z.L., B.Q., J.D.).

Circulation
|June 22, 2019
PubMed
Abstract

Insights

Myocardial ischemia-reperfusion (MI/R) injury is a critical condition. This study identifies S100a8/a9 as a key mediator of MI/R injury, offering a potential therapeutic target for heart attack recovery.

Area of Science:

  • Cardiovascular Research
  • Molecular Medicine
  • Proteomics and Genomics

Background:

  • Myocardial ischemia-reperfusion (MI/R) injury poses a significant clinical challenge with limited therapeutic options.
  • Unbiased omics approaches are crucial for identifying novel mediators of MI/R injury.

Purpose of the Study:

  • To identify early mediators of MI/R injury using dynamic transcriptome analysis.
  • To elucidate the role and mechanism of S100a8/a9 in MI/R injury.
  • To investigate the clinical relevance of S100a8/a9 in patients with acute myocardial infarction.

Main Methods:

  • Dynamic transcriptome analysis of mouse hearts subjected to MI/R.
  • Loss-of-function and gain-of-function studies of S100a8/a9.
  • Measurement of serum S100a8/a9 levels in MI patients post-PCI and follow-up for major adverse cardiovascular events.

Main Results:

  • S100a8/a9 was identified as the most upregulated gene during early reperfusion.
  • S100a9 knockout improved cardiac function, while overexpression worsened injury.
  • S100a8/a9 induced mitochondrial dysfunction by inhibiting Complex I via TLR4/ERK/PPARGC1A/NRF1 signaling.
  • S100a9 neutralizing antibody treatment reduced MI/R injury.
  • Elevated serum S100a8/a9 levels post-PCI in MI patients correlated with adverse cardiovascular events.

Conclusions:

  • S100a8/a9 is a critical regulator of cardiomyocyte death in early MI/R injury by suppressing mitochondrial function.
  • Targeting S100a8/a9-mediated signaling presents a promising novel therapeutic strategy for MI/R injury.
Keywords:
S100a8 proteinS100a9 proteinbiomarkersmyocardial reperfusion injurytherapeutic target

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