Targeting E3 Ubiquitin Ligase Hrd1 Prevents Myocardial Ischemia-Reperfusion Injury Through Enhancing ALDH2 Enzymatic Activity

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury presents a significant clinical challenge characterized by a complex pathological mechanism. The role of protein ubiquitination in I/R injury has not been systematically investigated. Global ubiquitinome profiling was conducted to identify the potential key players in myocardial I/R injury. METHODS: ), and EC-specific Hrd1 overexpression (AAV-EC-Hrd1) mice were used to assess the role of Hrd1 in myocardial I/R injury. Mass spectrometry and immunoprecipitation were used to elucidate the interaction between Hrd1 and aldehyde dehydrogenase 2 (ALDH2). Additionally, we assessed ubiquitination and vasomotor reactivity to clarify the mechanisms by which Hrd1 regulates ALDH2 activity and EC dysfunction during I/R injury. RESULTS: ECs and exacerbated endothelial dysfunction through the NO/cGMP/PKG (nitric oxide-cyclic guanosine monophosphate-protein kinase G) signaling pathway. Furthermore, our findings demonstrated that pharmacological inhibition of Hrd1 robustly ameliorated myocardial I/R injury and endothelial dysfunction. CONCLUSIONS: Our findings demonstrated a previously unidentified crucial role of cardiac EC Hrd1 in myocardial I/R injury. Hrd1 may serve as a therapeutic target for preventing myocardial I/R injury.