Plicamycin (PLI) is a small-molecule aureolic acid antibiotic that has been approved for cancer treatment since the 1970s. However, its interaction with cardiovascular biological systems during myocardial ischemia-reperfusion injury (MIRI) remains largely unknown. This study examines its cardioprotective effects and the mechanisms associated with cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in a murine MIRI model. PLI, administered intraperitoneally to mice at 150 μg/kg/day for seven days before cardiac ischemia-reperfusion, attenuated the rise in myocardial infarct size and serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels. PLI also improved cardiac function in MIRI mice, as reflected by higher ejection fraction (EF) and fractional shortening (FS) values. Biochemical assays and dihydroethidium (DHE) staining analyses showed that PLI administration prevented oxidative stress imbalance within the ischemic myocardium following reperfusion. PLI also prevented cardiomyocyte apoptosis within ischemic myocardial tissues by downregulating caspase-3, caspase-9, and Bax and upregulating Bcl-2 expression in MIRI mice. Further investigation showed that I/R injury reduced the expression levels of phospho-CREB and BDNF within the ischemic myocardium, both of which were prevented by PLI. More importantly, pharmacological suppression of CREB by 666-15 (10 mg/kg/day) or BDNF signaling by K252a (25 μg/kg/day) diminished the cardioprotective effects of PLI. Overall, our data suggest that PLI prevents I/R-induced cardiac injury by activating CREB-BDNF signaling, accompanied by suppression of nitro-oxidative stress.
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