title: H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart.
abstract: Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Medical School, Newark, NJ 07103, USA. deprech@umdnj.edu
authors.forename: Christophe
authors.initials: C
authors.lastname: Depre
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiangzhen
authors.initials: X
authors.lastname: Sui
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Nadia
authors.initials: N
authors.lastname: Hedhli
authors.forename: Audrey
authors.initials: A
authors.lastname: Ginion
authors.forename: Amy
authors.initials: A
authors.lastname: Shah
authors.forename: Michel
authors.initials: M
authors.lastname: Pelat
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.forename: Thomas
authors.initials: T
authors.lastname: Wagner
authors.forename: Vinciane
authors.initials: V
authors.lastname: Gaussin
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D050886:HSP20 Heat-Shock Proteins / Q000502:physiology*; D006360:Heat-Shock Proteins; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009097:Multienzyme Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000502:physiology*; D009203:Myocardial Infarction / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C490206:Hspb8 protein, mouse