Melatonin ameliorates myocardial ischemia/reperfusion injury via regulating the ubiquitin-proteasome system

Aims: Melatonin exerts cardioprotection in myocardial ischemia/reperfusion injury (MIRI) through anti-apoptotic effects. However, the underlying mechanisms remain incompletely elucidated. Growing evidence suggests that dysregulation of the ubiquitin-proteasome system (UPS) is closely associated with apoptotic. The aim of this study was to investigate whether melatonin can ameliorate MIRI by regulating UPS to inhibit Apoptosis.

Materials and methods: MIRI model and hypoxia/reoxygenation (H/R)-treated H9c2 cells were utilized in this research. Myocardial Apoptosis was assessed using western blotting, TUNEL assay, and flow cytometry, with parallel measurements of Proteasome subunits and ubiquitinated proteins levels. Echocardiography was employed to assess cardiac function, while Evans blue-TTC staining quantified infarct size.

Key findings: Melatonin activated the JAK2/STAT3 pathway, increased Proteasome subunits, and reduced the levels of ubiquitinated proteins, thereby improving UPS function to attenuate cardiomyocyte Apoptosis and restore cardiac function. Melatonin's anti-apoptotic effects were inhibited by the Proteasome Inhibitor bortezomib (BTZ). The JAK2 signaling inhibitor AG490 counteracted melatonin-induced upregulation of Proteasome subunits and reduction of ubiquitinated proteins, consequently reversing both its anti-apoptotic and cardioprotective effects.

Significance: Melatonin confers cardioprotection against MIRI via JAK2/STAT3-dependent UPS activation and subsequent Apoptosis inhibition. This provides new insights into the molecular basis of melatonin's cardioprotective properties.

Apoptosis; JAK2/STAT3; Melatonin; Myocardial ischemia/reperfusion; Ubiquitin-proteasome system.