Abstract 3368: Disruption of NF-kappa B Abrogates Cardioprotection Against Ischemia and Reperfusion Injury Elicited by Inhibition of Histone Deacetylases
Background: We have demonstrated that the inhibition of histone deacetylases (HDAC) protects heart against ischemia and reperfusion (I/R) injury. It has been shown that NF-kappa B p50 subunit is essential to induce a delayed cardioprotection. It remains unknown whether NF-kappa B was attributable to the protective effect elicited by inhibition of HDACs.
Our goal was to investigate role of HDAC inhibition to induce delayed cardioprotection and whether the disruption of NF-kappa B would eliminate protective effects by HDAC inhibition.
Methods: Wild type and NF-kappa B p50 knockout mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA) (0.1mg/kg, i.p.). Twenty four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia followed by 30 min of reperfusion. Left ventricular function was measured and infarct size was determined by triphenyltetrazolium chloride. Western blot was used to detect NF-kappa B protein following HDAC inhibition.
Results: Inhibition of HDACs by TSA produces the marked improvements in the left ventricular end-diastolic pressure (LVEDP), left ventricular rate pressure product (RPP) and reduction of infarct size as compared to non-TSA treated group (p<0.05). TSA- induced protection was absent with disruption of NF-kappa B p50 subunit as compared to TSA+B6.129 group. Western blot showed a significant nuclear accumulation of NF-kappa B p50 subunit and a remarkable acetylation of NF-kappa B p50 subunit at lysine residues following HDAC inhibition with TSA.
Conclusion: These results suggest that direct inhibition of HDACs triggers the cardioprotection, which is dependent on NF-kappa B.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).