Brain Death-Induced Donor Heart Injury Diminished by Melatonin Treatment via Suppressing DAMP Signaling

Purpose We test the hypothesis that melatonin diminishes brain death (BD)-induced donor heart injury by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling. Methods H9C2 cells or BD-derived brain tissue extract (BDEX)-treated H9C2 cells were co-cultured with BDEX (BDEX), healthy brain tissue extracts (sham control, SC) or reagent (NC) and Sprague-Dawley rats were divided into NC (healthy brain), BD, BD + Mel (BD rats treated with melatonin), and BD + Mel + Luz (BD rats treated with melatonin and its antagonist, luzindole) to check DAMP proteins, the downstream proinflammatory cytokines and the impact of melatonin on these inflammatory signaling protein levels. Additional rats were categorized into groups 1 NC (only left thoracotomy), 2 SC (healthy brain tissue extracts implanted into the LV myocardium (LVM)), 3 BDEX (BDEX implanted into the LVM), 4 BDEX-Mel (BDEX plus melatonin treatment) and 5 BDEX-Mel-Luz (BDEX plus melatonin and luzindole treatments) to assess the protective effect of melatonin against BD-induced myocardial injury by detecting cardiac inflammatory and immune cell infiltration, DNA damage, fibrosis, oxidative-stress, apoptosis, and transthoracic echocardiographic findings 5 days after BDEX implantation. Results Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. Levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1β, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. These increases were diminished by melatonin but re-induced with luzindole (all P Conclusion Brain death-induced donor heart injury might be diminished by melatonin suppressing the DAMP inflammatory axis.