title: Lumbrokinase attenuates myocardial ischemia-reperfusion injury by inhibiting TLR4 signaling.
abstract: Lumbrokinase, a novel antithrombotic agent, purified from the earthworm Lumbricus rubellus, has been clinically used to treat stroke and cardiovascular diseases. However, inflammatory responses associated with the cardioprotective effect of lumbrokinase remain unknown. In this study, the signaling pathways involved in lumbrokinase-inhibited expressions of inflammation mediators were investigated in rats subjected to myocardial ischemia-reperfusion (I-R) injury. The left main coronary artery of anesthetized rats was subjected to 1h occlusion and 3h reperfusion. The animals were treated with/without lumbrokinase and the severities of I-R-induced arrhythmias and infarction were compared. Lumbrokinase inhibited I-R-induced arrhythmias and reduced mortality, as well as decreased the lactate dehydrogenase levels in carotid blood. Lumbrokinase also inhibited the enhancement of I-R induced expressions of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and matrix metalloproteinase (MMP)-9 through toll-like receptor 4 (TLR4) signaling pathway. Moreover, our results demonstrated that stimulation with lumbrokinase decreases the phosphorylation of JNK, IκB, and NF-κB. These findings suggested that lumbrokinase is a potent cardioprotective drug in rats with I-R injury. The cardioprotective effects of lumbrokinase may be correlated with its inhibitory effect on the I-R-induced expressions of COX-2, iNOS and MMP-9, mediated by TLR4 signaling through JNK and NF-κB pathways.
authors: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors: Yi-Hsin
authors: YH
authors: Wang
authors: Department of Parasitology, Chung Shan Medical University, Taichung, Taiwan.
authors: Ke-Min
authors: KM
authors: Chen
authors: Department of Parasitology, Chung Shan Medical University, Taichung, Taiwan.
authors: Ping-Sung
authors: PS
authors: Chiu
authors: Department of Parasitology, Chung Shan Medical University, Taichung, Taiwan; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors: Shih-Chan
authors: SC
authors: Lai
authors: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming, University, Taipei, Taiwan.
authors: Hsing-Hui
authors: HH
authors: Su
authors: Institute of Biochemistry, Microbiology and Immunology, Medical College of Chung Shan Medical University, Taichung, Taiwan; Division of Allergy, Immunology, and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan; Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan.
authors: Ming-Shiou
authors: MS
authors: Jan
authors: Institute of Biochemistry, Microbiology and Immunology, Medical College of Chung Shan Medical University, Taichung, Taiwan.
authors: Chia-Wei
authors: CW
authors: Lin
authors: Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan.
authors: Dah-Yuu
authors: DY
authors: Lu
authors: School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Department of Chinese Medicine, Taichung Tzu Chi Hospital, The Buddhist Tzu Chi, Medical Foundation, Taichung, Taiwan.
authors: Yuan-Tsung
authors: YT
authors: Fu
authors: Department of Physiology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: jmliao@csmu.edu.tw.
authors: Jiuan-Miaw
authors: JM
authors: Liao
authors: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: jinghuat@csmu.edu.tw.
authors: Jinghua Tsai
authors: JT
authors: Chang
authors: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: sshuang@csmu.edu.tw.
authors: Shiang-Suo
authors: SS
authors: Huang
mesh_terms: D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D015415:Biomarkers; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004562:Electrocardiography; D010450:Endopeptidases / Q000494:pharmacology*; D006339:Heart Rate; D006439:Hemodynamics; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D001688:Biological Products; D015415:Biomarkers; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083421:lumbrokinase
keywords: Cardioprotection; Ischemia; Lumbrokinase; Reperfusion; TLR4