Abstract 3473: Down Regulation of Class I Histone Deacetylase in the Deficit of Cardiac Lineage Protein-1 Protects Heart from Ischemia Reperfusion Injury

Abstract

Cardiac lineage protein-1 (CLP-1), the mouse homologue of human Hexim1 protein, exerts inhibitory control over transcriptional elongation factor-b (P-TEFb) of RNA transcript elongation, and this inhibitory control of CLP-1 over P-TEFb is released under hypertrophic stimuli. Histone deacetylases (HDACs) are known to repress the transcription of genes via maintaining compact chromatin structure. Reports have shown that class II HDACs repress the growth of myocytes, whereas, class I HDACs promotes cellular growth. A recent report suggests that inhibition of HDACs can protect the heart from ischemic injury. In the present study, we determined the role of HDACs under the down regulation of CLP-1 in ischemia reperfusion (I/R) injury and in the regulation of cardiac hypertrophy. Our results showed that the nuclear expression of class I HDACs such as HDAC1, HADC2 and HDAC3 were reduced in CLP +/− mice compared to CLP +/+ mice. In contrast to class I HDACs, class II HDACs such as HDAC4, HDAC5 and HDAC7 were not significantly altered between CLP +/− and CLP +/+ mice. When the isolated mice hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion, cardiac functional parameters like aortic flow, left ventricular developed pressure and left ventricular dp/dt were significantly improved in CLP +/− mice compared to CLP +/+ mice. The percentage of myocardial infarct size after I/R injury was significantly less in CLP +/− mice than CLP +/+ mice. The occurrence of cardiac hypertrophy in CLP +/− mice was confirmed by the increased expression of fetal gene expression markers such as β-myosin heavy chain, atrial natriuretic factor and α-skeletal actin. The nuclear expression of HDAC1, HDAC2 and HDAC3 were reduced after I/R injury in CLP +/− mice compared to control CLP +/− mice. However, HDAC4, HDAC5 and HDAC7 were not altered after I/R injury in CLP +/− mice. In conclusion, our results suggest that the down regulation of class I HDACs but not class II HDACs in CLP-1 +/−mice could cause cardioprotection against I/R injury, and may also responsible for the elicitation of cardiac hypertrophy.