title: Toll-interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis.
abstract: OBJECTIVE
  Toll-interacting protein (Tollip) is an endogenous inhibitor of toll-like receptors, a superfamily that plays a pivotal role in various pathological conditions, including myocardial infarction (MI). However, the exact role of Tollip in MI remains unknown.
  
  
  METHODS
  MI models were established in Tollip knockout (KO) mice, mice with cardiac-specific overexpression of human Tollip gene and in their Tollip(+/+) and non-transgenic controls respectively. The effects of Tollip on MI were evaluated by mortality, infarct size and cardiac function. Hypoxia-induced cardiomyocyte damage was investigated in vitro to confirm the role of Tollip in heart damage.
  
  
  RESULTS
  Tollip expression was dramatically up-regulated in human ischaemic hearts and infarcted mice hearts. MI-induced mortality, infarct size and cardiac dysfunction were decreased in Tollip-KO mice compared with Tollip(+/+) controls. Ischaemic hearts from Tollip-KO mice exhibited decreased inflammatory cell infiltration and reduced NF-κB activation. Tollip depletion also alleviated myocardial apoptosis by down-regulating pro-apoptotic protein levels and up-regulating anti-apoptotic protein expressions in infarct border zone. Conversely, MI effects were exacerbated in mice with cardiac-specific Tollip overexpression. This aggravated MI injury by Tollip in vivo was confirmed with in vitro assays. Inhibition of Akt signalling was associated with the detrimental effects of Tollip on MI injury; activation of Akt largely reversed the deleterious effects of Tollip on MI-induced cardiomyocyte death.
  
  
  CONCLUSIONS
  Tollip promotes inflammatory and apoptotic responses after MI, leading to increased mortality and aggravated cardiac dysfunction. These findings suggest that Tollip may serve as a novel therapeutic target for the treatment of MI.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Wan
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Gangying
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Emergency, The Second Artillery General Hospital of Chinese People's Liberation Army Qinghe Clinic, Beijing, China.
authors.forename: Fengwei
authors.initials: F
authors.lastname: Wan
authors.affiliation: Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human; C485837:Tollip protein, mouse