The transcription factor PPARA mediates SIRT1 regulation of NCOR1 to protect damaged heart cells

Heart failure (HF) is a clinical syndrome with a high risk. Our previous research showed a regulatory relationship between Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor α (PPARA) and nuclear receptor co-repressor 1 (NCOR1). This study aimed to investigate the regulatory mechanism of SIRT1/PPARA/NCOR1 axis in HF.

This study revealed that PPARA could mediate SIRT1 to promote NCOR1 expression and thus protect damaged heart cells. The finding provided an important reference for the treatment of HF.

HF models in vitro were established by doxorubicin (DOX)-induced AC16 and human cardiac microvascular endothelial cell (HCMEC) lines. The contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), interleukin-1β (IL-1β), and IL-18 were detected using enzyme-linked immunosorbent assay. Then, we assessed the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and adenosine triphosphate (ATP). Moreover, the relationship between SIRT1 and PPARA was detected using the co-immunoprecipitation (Co-IP) analysis. The connection between PPARA and NCOR1 was analyzed using chromatin immunoprecipitation (ChIP).

Overexpression of SIRT1 or PPARA could reduce apoptosis in DOX-induced AC16 and HCMEC cells, the levels of IL-1β, IL-18, ANP, BNP, ROS and MDA, while increasing the levels of SOD and ATP. In addition, overexpression of PPARA could increase the viability of DOX-induced cells and the levels of myosin heavy chain 6 (Myh6) and Myh7. Co-IP showed that SIRT1 interacted with PPARA. Silencing PPARA could reverse the effect of SIRT1 overexpression on DOX-induced AC16 and HCMEC cells. ChIP assay demonstrated that PPARA could bind to the promoter region of NCOR1. Silencing NCOR1 could reverse the effect of PPARA overexpression on DOX-induced AC16 and HCMEC cells. Conclusions: This study revealed that PPARA could mediate SIRT1 to promote NCOR1 expression and thus protect damaged heart cells. The finding provided an important reference for the treatment of HF.