Abstract
Background: Protein quality control (PQC) in the heart plays an important role to maintain cellular protein homeostasis. Impaired PQC accumulates misfolded proteins and their aggregates, leading to heart failure. Three major pathways such as refolding of misfolded proteins by heat shock proteins (HSPs), proteolysis of misfolded proteins through the ubiquitin-proteasome system, and degradation of protein aggregates via the autophagy-lysosome system are involved in PQC. It has been suggested that histone deacetylase 6 (HDAC6) involves in all three pathways. However, the association between HDAC6 and PQC in the development of heart failure is unknown. In this study, to examine the role of HDAC6 in the development of heart failure following myocardial infarction (MI), we focused on misfolded protein repair by HSPs.
Methods: MI was induced by coronary artery ligation (CAL). Oral administration of the Sham and CAL rats with 50 mg/kg/day of suberoylanilide hydroxamic acid (SAHA) or vehicle were undertaken from the 2nd (2W) to the 8th week (8W) after the operation. Protein contents in the viable left ventricle were determined by western immunoblotting.
Results: Hemodynamic parameters at the 8W, but not 2W, after CAL showed signs of chronic heart failure. Myocardial HDAC6 activity in 8W-CAL rats was elevated compared to that in 2W-CAL rats. HSP90 complex includes heat shock transcription factor 1 (HSF1), which regulates HSP contents such as HSP72, HSPB1 and HSPB5. Acetylation of HSP90 enhances to release HSF1 from HSP90 complex. Myocardial HSP contents in 2W-CAL rats were increased, whereas HSP contents in 8W-CAL rats were similar to those in the corresponding Sham rats. These results suggest that HSP90 deacetylation is accelerated by an increase in HDAC6 activity in the failing heart. Then we administered an HDAC inhibitor SAHA to CAL rats. SAHA treatment of CAL rats attenuated the reduction in myocardial HSP contents during the development of heart failure. The cardiac pump function after MI was also preserved by SAHA treatment.
Conclusions: These results suggest that HDAC6 inhibition by SAHA increases HSP contents through acetylation of HSP90, contributing to preserve cardiac contractile function after MI.
