Sevoflurane suppresses circ_SMG6 to inhibit TLR4/mTOR signaling and attenuate myocardial ischemia-reperfusion injury

Background Myocardial ischemia-reperfusion injury (MIRI) is a main contributor to adverse effects after acute myocardial infarction. Sevoflurane provides cardioprotection, however the link of role Sevoflurane with circular RNAs, particularly circ_SMG6, and interaction with TLR4/mTOR signaling is unknown.Methods Sprague-Dawley rats were divided into Sham, MIRI, or sevoflurane+MIRI groups and the Myocardial infarct size, histopathology, and myocardial apoptotic nuclei in rat hearts were measured by 2,3,5-Triphenyltetrazolium Chloride (TTC) staining, Hematoxylin and Eosin (H&E), and TUNEL staining. Additionally, circ_SMG6 and TLR4/mTOR expression were quantified by qRT-PCR and Western blotting. In order to assess viability, apoptosis, inflammatory cytokines, and TLR4/mTOR signaling readout, human cardiomyocytes were transfected with circ_SMG6 overexpression or knockdown vectors 48 h before hypoxia-reoxygenation (H/R) induction, either with or without sevoflurane.Results MIRI increased the myocardial apoptotic index, infarct size, and structural cardiac damage with elevated circ_SMG6 and TLR4/mTOR signaling. These alterations were lessened with sevoflurane, although they were not entirely restored. H/R increased circ_SMG6, improved TLR4/mTOR signaling readout, reduced viability, and increased TNF α/IL 1β/IL 6 production in AC16 and HCM cells. circ_SMG6 knockdown reversed these effects, whereas circ_SMG6 overexpression further aggravated H/R-induced injury, supporting the functional involvement of circ_SMG6 in TLR4/mTOR-associated inflammatory and apoptotic responses. Sevoflurane treatment phenocopied circ_SMG6 silencing at both functional and signaling levels.Conclusions circ_SMG6 may exacerbate MIRI through TLR4/mTOR-associated inflammatory and apoptotic signaling in cardiomyocytes, while sevoflurane attenuates myocardial injury, at least in part, by suppressing this circ_SMG6-related pathway. These findings identify circ_SMG6 as a potential therapeutic target in sevoflurane-based cardioprotection against MIRI.