title: Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury.
abstract: Ischemic heart disease is a leading cause of death in human population and protection of myocardial infarction (MI) associated with ischemia-reperfusion (I/R) remains a challenge. MG53 is an essential component of the cell membrane repair machinery that protects injury to the myocardium. We investigated the therapeutic value of using the recombinant human MG53 (rhMG53) protein for treatment of MI. Using Langendorff perfusion of isolated mouse heart, we found that I/R caused injury to cardiomyocytes and release of endogenous MG53 into the extracellular solution. rhMG53 protein was applied to the perfusion solution concentrated at injury sites on cardiomyocytes to facilitate cardioprotection. With rodent models of I/R-induced MI, we established the in vivo dosing range for rhMG53 in cardioprotection. Using a porcine model of angioplasty-induced MI, the cardioprotective effect of rhMG53 was evaluated. Intravenous administration of rhMG53, either prior to or post-ischemia, reduced infarct size and troponin I release in the porcine model when examined at 24h post-reperfusion. Echocardiogram and histological analyses revealed that the protective effects of rhMG53 observed following acute MI led to long-term improvement in cardiac structure and function in the porcine model when examined at 4weeks post-operation. Our study supports the concept that rhMG53 could have potential therapeutic value for treatment of MI in human patients with ischemic heart diseases.
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Yongqiu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Protein Therapeutics Division, TRIM-edicine, Inc., North Brunswick, NJ.
authors.forename: Tao
authors.initials: T
authors.lastname: Tan
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Jincai
authors.initials: J
authors.lastname: Hou
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, Ohio.|Protein Therapeutics Division, TRIM-edicine, Inc., North Brunswick, NJ.
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.affiliation: School of Life Sciences, Peking University, Beijing, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Peihui
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, the Ohio State University Wexner Medical Center, Columbus, Ohio.|Protein Therapeutics Division, TRIM-edicine, Inc., North Brunswick, NJ.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D000070584:Tripartite Motif Proteins
chemical_list: D002316:Cardiotonic Agents; D002352:Carrier Proteins; D011994:Recombinant Proteins; C558399:TRIM72 protein, human; D000070584:Tripartite Motif Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Angioplasty; Cell membrane repair; Myocardial infarction; Myocardial ischemia; TRIM72