Ferulic Acid Limits Ischemia-Reperfusion Injury: Proteasome and Adenosine Monophosphate-Activated Protein Kinase–Dynamin-Related Protein 1 Effects

Myocardial ischemia/reperfusion injury (I/RI) remains a major limitation of reperfusion therapy. This study examined whether proteasome-associated changes and mitochondrial dynamics accompany the cardioprotective effect of ferulic acid (FA). Mice underwent left anterior descending coronary artery ligation for 30 min followed by 24 h of reperfusion. FA was administered before ischemia, and epoxomicin was used as a pharmacological inhibitor of the proteasome. Cardiac function, infarct size, apoptosis, histopathology, oxidative stress, proteasome catalytic activity, immunoproteasome subunit abundance, and mitochondrial morphology were assessed. I/R reduced cardiac function, all three measured proteasome activities, and the abundance of low molecular mass polypeptide 2 (LMP2), LMP10, and LMP7, while increasing myocardial injury and mitochondrial fission. FA at 20 mg/kg improved these quantitative outcomes and was associated with higher adenosine monophosphate-activated protein kinase alpha subunit (AMPKα) phosphorylation, lower dynamin-related protein 1 (Drp1) Ser616 phosphorylation, and greater mitofusin 1/2 (Mfn1/2) abundance. Epoxomicin aggravated injury and signaling abnormalities, whereas FA retained partial protection. Thus, the pharmacological data support a proteasome-associated component of FA cardioprotection linked to AMPK-Drp1-related mitochondrial dynamics, while also indicating that additional proteasome-independent actions may contribute.