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Inhibition of the RNA binding protein HuR reduces cardiac cell death following ischemia/reperfusion injury
Author(s) -
Slone Samuel,
Anthony Sarah R.,
Lanzillotta Lindsey,
Nieman Michelle L.,
Green Lisa C.,
Lorenz John N.,
Tranter Michael
Publication year - 2018
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.2018.32.1_supplement.717.26
Subject(s) - myocyte , reperfusion injury , ischemia , myocardial infarction , medicine , apoptosis , ligation , p38 mitogen activated protein kinases , reactive oxygen species , cardiology , mapk/erk pathway , microbiology and biotechnology , biology , signal transduction , biochemistry
Despite medical advances, ischemic cardiac injury (ischemia/reperfusion (I/R) injury or myocardial infarction) remains a leading cause of morbidity and huge economic burden in the United States. It is known that the extent of total damage to the heart following I/R injury is directly linked to the percentage of affected individual cardiac myocytes that undergo apoptotic cell death. 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. It is widely accepted that after an ischemic injury, reperfusion, the return of blood flow and therefore oxygen, introduces reactive oxygen species (ROS) that further activates downstream pro‐apoptotic pathways. We have previously shown HuR to be activated downstream of p38 MAPK in cardiac myocytes; since p38 MAPK is known to be downstream of ROS, we postulated that HuR is a potential mediator of apoptotic gene expression during cardiac I/R injury. To address the functional role of HuR in I/R, we utilized an inducible cardiomyocyte‐specific HuR deletion mouse (iCM‐HuR −/− ) and subjected these mice to 30 minutes of LAD (left anterior descending artery) ligation followed by 24 hours of reperfusion. Analysis of infarct size showed that iCM‐HuR −/− mice had a significantly smaller infarct compared to control mice (41% infarct/risk in iCM‐HuR −/− vs. 51% infarct/risk in control, N=3, P<0.05). To identify an underlying mechanism for this cardioprotective effect, we performed simulated I/R (simI/R) in vitro on neonatal rat ventricular myocytes (NRVMs) by subjecting them to 6 hrs of simulated ischemia (glucose deprivation and hypoxia at ≤1% O 2 ) followed by 24 hrs of reperfusion (reoxygenation and reintroduction of glucose). Similar to our in vivo results, siRNA‐mediated knockdown or pharmacological inhibition of HuR significantly reduced simI/R‐induced cell death and caspase‐3 activity. We also observed an increase in expression of key apoptotic genes (Bcl‐2, Bad, and Bax) in NRVMs following simI/R, and ongoing work will identify the specific role of HuR in mediating expression of these genes. In conclusion, our results suggest that ablation of HuR results in a significant reduction in infarct size following I/R injury through a reduction in caspase 3‐dependent apoptotic cell death. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .