Breaking the vicious cycle: Avasopasem manganese disrupts ER Stress-Oxidative damage crosstalk in ischemic cardiac injury in type 1 diabetic mice.

European journal of pharmacology 2026

Kutlu Z, Halici Z, Tavaci T, Karcioğlu SS, Yildirim S, Bayraktutan Z, Celik Z

Abstract

This study aimed to investigate the effects of avasopasem manganese (AVA), a superoxide dismutase (SOD) mimetic, on endoplasmic reticulum stress (ERS) in isoproterenol (ISP)-induced ischemic heart injury in type 1 diabetic male mice. Oxidative stress (OS) and ERS are known to play important roles in the progression of cardiac damage, and diabetes mellitus (DM) itself exacerbates ERS. It is postulated that agents capable of inhibiting ERS many alleviate ischemic heart injury. This study investigated the effects of AVA on ischemic heart injury in type 1 diabetic mice via ERS-related proteins (GRP78, PERK, IRE1, ATF4, XBP1, Nrf2, and CHOP/caspase 12). A power analysis determined that 96 male BALC-c mice, aged 6-8 weeks, were utilized and randomly allocated into six groups: control, DM, ISP, DM + AVA (10 mg/kg), ISP + AVA (10 mg/kg), and DM + ISP + AVA (10 mg/kg). In diabetic and ischemic mice, AVA treatment raised the levels of glutathione (GSH) and the activities of the enzymes superoxide dismutase (SOD) and catalase (CAT). It also lowerd the levels of malondialdehyde (MDA) and the activity of myeloperoxidase (MPO). Cardiac markers creatine kinase-muscle type/brain type isoenzyme (CK-MB) and cardiac troponin T (cTnT) levels were also decreased following treatment. In the diabetic and ischemic mice, mRNA expression of ERS-related proteins (GRP78, PERK, IRE1, ATF4, XBP1, and Nrf2) was elevated but significantly reduced after AVA administration. AVA treatment improved cardiac outcomes by reducing OS and inflammation and downregulating ERS-related protein expression in diabetic and ischemic mice.

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