Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling

// Pei-Hsun Sung 1, * , Fan-Yen Lee 2, * , Ling-Chun Lin 1 , Kuan-Hung Chen 3 , Hung-Sheng Lin 4 , Pei-Lin Shao 5 , Yi-Chen Li 1 , Yi-Ling Chen 1 , Kun-Chen Lin 3 , Chun-Man Yuen 6 , Hsueh-Wen Chang 7 , Mel S. Lee 8 and Hon-Kan Yip 1, 5, 9, 10, 11 1 Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 3 Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 4 Division of Neurology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Nursing, Asia University, Taichung, Taiwan 6 Division of Neurosurgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 8 Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 9 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 10 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 11 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Hon-Kan Yip, email: han.gung@msa.hinet.net Keywords: brain death; damage-associated molecular patterns; inflammation; remote organ; heart function Received: October 02, 2017      Accepted: December 01, 2017      Published: December 12, 2017 ABSTRACT We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, 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. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P < 0.001). Additional male rats ( n = 30) were divided into groups 1 (negative control), 2 (healthy brain tissue extract implanted in the left ventricular myocardium [LVM]), 3 (BDEX-LVM), 4 (BDEX-LVM + melatonin), and 5 (BDEX-LVM + melatonin + luzindole). Collagen deposition/fibrosis and LVM levels of MTR2, HMGB1, inflammatory markers, oxidative stress, apoptosis, mitochondrial damage and DNA damage were highest in group 3, lowest in groups 1 and 2, and higher in group 5 than in group 4. Heart function and LVM levels of MTR1 and anti-inflammatory, mitochondrial-integrity and anti-oxidative markers exhibited a pattern opposite that of the inflammatory markers in the five groups (all P < 0.0001). These results indicate melatonin inhibits BDEX-induced cardiac damage by suppressing the DAMP inflammatory axis.