The human S100A9 gene encodes the S100 calcium-binding protein A9 (S100A9). In mammals, S100A8 and S100A9 proteins form a heterodimer known as calprotectin. Calprotectin is involved in the inflammatory process - it is known to be present as a soluble protein in the cytosol of neutrophil granulocytes, and is found in lower concentrations among in monocytes, macrophages, and squamous epithelial cells. The following study has identified S100a8/a9 as key mediators of early myocardial ischemia-reperfusion (MI/R) injury that may serve as potential therapeutic intervention targets.

 

Featured Citation Review - S100a8/a9 promotes ischemic/ reperfusion injury

Title: S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocytes Death in Response Ischemic/Reperfusion Injury

Journal: Circulation

Impact factor (IF): 23.054

Publication Date: 2019.06.21

Selected product: S100a9 knockout (KO) mice

 

Research Approach:

Step 1  Dynamic transcriptomic analysis

Researchers performed time series transcriptomic analysis to learn the dynamic pathological alterations of mouse hearts at different stages of MI/R. Dynamic transcriptomic analysis screened and identified S100a8/a9, an inflammatory molecule, as the key mediator of MI/R injury. In the early reperfusion stage, S100a8/a9 was identified as the most significant up-regulated gene – its expression was confirmed via immunochemistry and reverse-transcriptase PCR in mice hearts after I/R.

 Dynamic transcriptomic analysis on mouse hearts at different stages of MI/R, and identified S100a8/a9 is a dynamically regulated key mediator of MI/R injury. Mice were subjected to myocardial infarction (MI), followed by different lengths of reperfusion (R) periods

Figure 1.  Dynamic transcriptomic analysis on mouse hearts at different stages of MI/R, and identified S100a8/a9 is a dynamically regulated key mediator of MI/R injury. Mice were subjected to myocardial infarction (MI), followed by different lengths of reperfusion (R) periods.

  

Step 2  Function loss/gain experiment

Researchers used both the loss- and gain-of-function approaches to study the role of S100a8/a9 in MI/R injury. For these approaches, S100a9 gene knockout (KO) mice and S100a9 transgenic (TG) overexpression mice models were implemented for comparison with wild-type (WT) mice. S100a9 gene knockout (KO) was shown to significantly reduce cardiomyocyte (CM) death, decrease infarct size, and improve cardiac function, while S100a9 overexpression aggravates MI/R injury. These results indicate that S100a8/a9 is critical for the sequelae of I/R-induced myocardial death, adverse cardiac remodeling, and heart failure.

S100a8/ A9 promotes cardiomyocyte death and heart failure during MI/R

Figure 2. S100a8/ A9 promotes cardiomyocyte death and heart failure during MI/R

 

Step 3  Transcriptomic and functional experiments

To further explore the mechanism of action of S100a8/a9, the researchers conducted transcriptomic and functional experiments. The results show that S100a8/a9 leads to cardiac mitochondrial respiratory dysfunction. S100a8/a9 down-regulates NDUF gene expression with subsequent mitochondrial complex I inhibition via Toll-like receptor 4(TLR4)/Erk–mediated Pparg coactivator 1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1) signaling suppression. S100a9 neutralizing antibody is shown to significantly reduce MI/R injury and improve cardiac function.

 Blocking S100a9 inhibits MI/R injury

Figure 3. Blocking S100a9 inhibits MI/R injury

 

Step 4  Clinical research verification

In order to examine the clinical correlation between the elevated S100a8/a9 and MI/R injury, the researchers evaluated the dynamic changes of serum S100a8/a9 levels after percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients and its predictive value for major cardiovascular events (MACEs). It was found that the serum S100a8/a9 level was significantly increased on the first day post-PCI in AMI patients, indicating that the increase in S100a8/a9 level was related to the incidence of major adverse cardiovascular events.

 

Conclusions:

This study demonstrates for the first time that S100a8/a9 directly promotes CM death after I/R by a novel intracellular mechanism which involves mitochondrial complex I dysfunction. Clinical research has shown that increased levels of S100a8/a9 after PCI are associated with poor prognosis in patients with AMI. Overall, these findings indicate S100a8/a9 to be a key regulator of CM death in early MI/R injury, and that S100a8/a9-initiated signaling may serve as both a new therapeutic intervention target and a useful prognostic biomarker for MI/R injury.

 

About Cyagen

The world's leading provider of transgenic and knockout mouse and rat services, with thousands of genetically modified mice generated each year for researchers worldwide. Cyagen has been cited in over 3,600 publications across highly reputed peer-reviewed journals such as NatureJCICancer cellImmunity, and more.