Abstract
Protein quality control (PQC) in the heart plays an important role to maintain cellular protein homeostasis. Impairment of PQC may cause the development of heart failure. It is well known that histone deacetylase 6 (HDAC6) is an essential enzyme for regulating the cellular PQC response. In this study, we aimed at examining the association between HDAC6 and the chaperone system and the effects of HDAC6 inhibition in the development of heart failure following myocardial infarction (MI). MI was induced by coronary artery ligation. Coronary artery-ligated and sham-operated rats were divided into groups that were orally administered suberoylanilide hydroxamic acid (SAHA) or vehicle from the 2nd to 8th week after the operation. The cardiac function and protein expression levels in the viable left ventricle were analyzed by echocardiography, Western blotting, and immunohistochemistry at the 2nd and 8th weeks after the operation. The deacetylase activity of HDAC6 was markedly elevated during the development of heart failure after MI. In the failing heart, a decrease in heat-shock protein (HSP) contents and an accumulation of ubiquitinated proteins were observed, indicating PQC dysfunction. Inhibition of HDAC6 activity by SAHA treatment enhanced the translocation of heat-shock transcription factor 1 to the nucleus and induced the expression of HSP, resulting in maintenance of cellular protein homeostasis. The cardiac pump function after MI was also improved by SAHA administration. Our findings suggest that inhibition of HDAC6 activity is a novel approach for the treatment of heart failure following MI.