Abstract

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (Hace1) is a crucial mediator of multiple pathological disorders. However, there are few studies regarding the role of Hace1 in myocardial ischemia/reperfusion injury. Here, we studied the functional role of Hace1 on myocardial ischemia/reperfusion injury using hypoxia/reoxygenation (H/R)-injured cardiac cells in vitro. Reduced levels of Hace1 were observed in H/R-exposed cardiac cells. Hace1-overexpressed cardiac cells were resistant to H/R injuries with reduced apoptosis, lowered oxidative stress, and a suppressed inflammatory response. Subsequent analysis revealed that Hace1 overexpression enhanced the activation of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and increased the transcriptional activity of Nrf2 in H/R-exposed cardiac cells. The knockout of kelch-like ECH-associated protein 1 (Keap1) diminished the regulatory role of Hace1 on Nrf2 activation. Additionally, inhibiting Nrf2 reversed Hace1-elicited cardioprotective effects in H/R-injured cardiac cells. In short, these data demonstrated that Hace1 overexpression mitigated myocardial H/R injury by enhancing the Nrf2 pathway via Keap1. This work underlines a possible role of Hace1 in myocardial ischemia/reperfusion injury and suggests Hace1 as a candidate target for exploiting cardioprotective therapy.