Role of sevoflurane in myocardial ischemia-reperfusion injury via the ubiquitin-specific protease 22/lysine-specific demethylase 3A axis

Abstract

Myocardial ischemia-reperfusion injury (MIRI) represents a coronary artery disease, accompanied by high morbidity and mortality. Sevoflurane post-conditioning (SPC) is importantly reported in myocardial disease. Accordingly, the current study sought to evaluate the role of Sevo in MI/RI. Firstly, MI/RI models were established and subjected to SPC. Subsequently, pathological injury in the myocardium, myocardial infarction areas, H9c2 cell viability, apoptosis, and levels of creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH) were all measured. Ubiquitin-specific peptidase (22USP22), lysine-specific demethylase 3A (KDM3A), and Yes1 associated transcriptional regulator (YAP1) were down-regulated in H9c2 cells using cell transfection to verify their roles. The interaction between USP22 and KDM3A and between KDM3A and YAP1 was further validated. USP 22, KDM3A, and YAP1 were found to be down-regulated in MI/RI and SPC protected MI/RI rats, as evidenced by up-regulated expressions of USP22, KDM3A, and YAP1, reduced pathological injury in the myocardium, myocardial infarction areas, apoptosis, and levels of CK-MB, cTnI, and LDH, and enhanced H9c2 cell viability; while the protective effects of Sevo were counteracted by silencing of USP22, KDM3A, and SPC upregulated USP22, which stabilized KDM3A protein levels via deubiquitination, and KDM3A inhibited histone 3 lysine 9 di-methylation (H3K9me2) levels in the YAP1 promoter to encourage YAP1 transcription, to reduce MI/RI.

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

“…Moreover, the Yes1-associated transcriptional regulator ( Yap1 ) leads to myofibroblast activation after myocardial infarction, and YAP1, accompanied by Foxm1 , participates in various hypertrophic and fibrotic disorders [ 31 ]. YAP1 and Foxm1 upregulation reduces pathological injury in the myocardium [ 43 , 44 ]. In contrast, the cardiac expression of Yap1 and Foxm1 increases under hyperglycemic conditions leading to cardiomyocyte hypertrophy and fibrotic responses through increased AKT phosphorylation and Glycogen synthase kinase-3 beta inhibition [ 31 ].…”

USP38 exacerbates pressure overload-induced left ventricular electrical remodeling

“…The ubiquitin–proteasome system (UPS) regulates protein degradation, cell signaling, and other cellular processes through a reversible process to target proteins. USP plays a regulatory role in cardiac diseases such as myocardial infarction, cardiac hypertrophy, and ischemic heart disease (Song et al 2022 ; Heitmeier et al 2020 ). Although the role of USP38 in tumors, respiratory diseases and myocardial infarction has been previously studied, its role in VAs after HF has not yet been completely elucidated (Gong et al 2023 ).…”

The role of deubiquitinases in cardiac disease

“…The upregulation of USP22 indirectly promoted the transcription of YAP1, thereby reduced myocardial cell injury (Ref. 96 ).…”