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Inhibition of the RNA binding protein HuR protects against cardiac ischemia/reperfusion injury by reducing inflammatory gene expression
Author(s) -
Slone Samuel,
Fleifil Salma,
Anthony Sarah,
Green Lisa,
Nieman Michelle L,
Lorenz John,
Tranter Michael
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb515
Subject(s) - ischemia , myocyte , reperfusion injury , medicine , chemokine , myocardial infarction , cardiology , ligation , pharmacology , inflammation
Despite medical advances, cardiac ischemia/reperfusion (I/R) injury remains a leading cause of morbidity and a huge economic burden in the United States. RNA binding proteins are becoming recognized as potential mediators of cardiac physiology and pathology, but the role of HuR, an RNA binding protein highly expressed in myocytes, in acute cardiac I/R injury is unknown. HuR has been shown in other tissues to be a critical post‐transcriptional mediator of pro‐inflammatory chemokine and cytokine gene expression, and our lab has shown HuR to be activated (nuclear‐to‐cytoplasmic translocation) in cardiomyocytes 2 hours post‐ischemia/reperfusion injury. To address the functional role of HuR in I/R, cardiomyocyte‐specific HuR deletion mice (iCM‐HuR −/− ) were subjected to 30 minutes of LAD (left anterior descending) coronary artery ligation followed by 24 hours of reperfusion. In parallel, a separate group of wild‐type mice were subjected to 30 minutes ischemia with a pharmacological inhibitor of HuR given just prior to reperfusion. Analysis of infarct size showed a smaller infarct with both HuR genetic deletion (41% infarct/risk in iCM‐HuR −/− vs. 51% infarct/risk in control, N=3, P<0.05) and pharmacological inhibition (~11% decrease in infarct size compared to vehicle, N=4, P=0.069). We were also able to recapitulate this protection in vitro using neonatal rat ventricular myocytes (NRVMs) and H9C2s (myoblast derived rat left ventricular cardiomyocytes) subjected to 6 hrs of simulated ischemia (glucose deprivation and hypoxia at ≤1% O 2 ) followed by 2 or 24 hrs of reperfusion (reoxygenation and reintroduction of glucose/serum) by showing that siRNA‐mediated knockdown or pharmacological inhibition of HuR significantly reduced cell death and caspase‐3 activation. Analysis of inflammatory gene expression demonstrates a significant blunting of IL‐6 expression at just two hours post‐reperfusion both in vivo and in vitro, suggesting that HuR activity is necessary for the early induction of inflammatory gene expression networks. In conclusion, our results suggest that inhibition of HuR is protective against cardiac I/R injury through a reduction in inflammatory gene expression. Work is still ongoing to identify the specific means by which HuR is activated and mediating expression of inflammatory cytokines and chemokines. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .