Daily melatonin protects the endothelial lineage and functional integrity against the aging process,oxidative stress,and toxic environment and restores blood flow in critical limb ischemia area in mice |
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| Authors: | Fan‐Yen Lee Cheuk‐Kwan Sun Pei‐Hsun Sung Kuan‐Hung Chen Sarah Chua Jiunn‐Jye Sheu Sheng‐Ying Chung Han‐Tan Chai Yi‐Ling Chen Tien‐Hung Huang Chi‐Ruei Huang Yi‐Chen Li Chi‐Wen Luo Hon‐Kan Yip |
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| Institution: | 1. Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;2. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;3. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;4. Division of Cardiovascular Surgery, Department of Surgery, Tri‐Service General Hospital, National Defense Medical Center, Taipei, Taiwan;5. Department of Emergency Medicine, E‐Da Hospital, I‐Shou University School of Medicine for International Students, Kaohsiung, Taiwan;6. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;7. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;8. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan;9. Department of Nursing, Asia University, Taichung, Taiwan |
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| Abstract: | We tested the hypothesis that daily melatonin treatment protects endothelial lineage and functional integrity against the aging process, oxidative stress/endothelial denudation (ED), and toxic environment and restored blood flow in murine critical limb ischemia (CLI). In vitro study using HUVECs, in vivo models (ie, CLI through left femoral artery ligation and ED through carotid artery wire injury), and model of lipopolysaccharide‐induced aortic injury in young (3 months old) and aged (8 months old) mice were used to elucidate effects of melatonin treatment on vascular endothelial integrity. In vitro study showed that menadione‐induced oxidative stress (NOX‐1/NOX‐2), inflammation (TNF‐α/NF‐kB), apoptosis (cleaved caspase‐3/PARP), and mitochondrial damage (cytosolic cytochrome c) in HUVECs were suppressed by melatonin but reversed by SIRT3‐siRNA (all P < .001). In vivo, reduced numbers of circulating endothelial progenitor cells (EPCs) (C‐kit/CD31+/Sca‐1/KDR+/CXCR4/CD34+), and angiogenesis (Matrigel assay of bone marrow‐derived EPC and ex vivo aortic ring cultures) in older (compared with younger) mice were significantly reversed through daily melatonin administration (20 mg/kg/d, ip) (all P < .001). Aortic vasorelaxation and nitric oxide release were impaired in older mice and reversed in age‐match mice receiving melatonin (all P < .01). ED‐induced intimal/medial hyperplasia, reduced blood flow to ischemic limb, and angiogenesis (reduced CD31+/vWF+ cells/small vessel number) were improved after daily melatonin treatment (all P < .0001). Lipopolysaccharide‐induced aortic endothelial cell detachment, which was more severe in aged mice, was also alleviated after daily melatonin treatment (P < .0001). Daily melatonin treatment protected both structural and functional integrity of vascular endothelium against aging‐, oxidative stress‐, lipopolysaccharide‐, and ischemia‐induced damage probably through upregulating the SIRT signaling pathway. |
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| Keywords: | angiogenesis endothelial cells endothelial progenitor cells ischemia melatonin oxidative stress |
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