USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis.

Abstract

Coronary microembolization (CME) is a serious cardiovascular complication that causes severe cardiac dysfunction and arrhythmias. Glutathione (GSH) exhaustion-induced oxidative stress is a key contributor to CME. Here, we explore the molecular mechanisms underlying GSH imbalance during CME. We show that CME induces myocardial injury by disturbing GSH homeostasis, which is ameliorated by glutamate-cysteine ligase modifier subunit (GCLM) or glutaminase (GLS) overexpression. Lysine-specific histone demethylase 1A (KDM1A) removes H3K9me1/2 from the promoter regions of GCLM and GLS to promote their epigenetic expression, thereby maintaining GSH homeostasis in CME. KDM1A is ubiquitinated at the K355 site during CME via inhibiting ubiquitin-specific peptidase 16 (USP16)-mediated deubiquitination. Inducible nitric oxide synthase (iNOS) facilitates S-nitrosylation (SNO) of USP16 at the C731 site, contributing to KDM1A ubiquitination and causing GSH imbalance during CME. Altogether, SNO-USP16 inhibition stabilizes the KDM1A protein to epigenetically activate GCLM and GLS, thus maintaining GSH homeostasis and relieving CME-induced myocardial injury.