title: c-Jun N-terminal kinase (JNK-1) confers protection against brief but not extended ischemia during acute myocardial infarction.
abstract: Brief periods of ischemia do not damage the heart and can actually protect against reperfusion injury caused by extended ischemia. It is not known what causes the transition from protection to irreversible damage as ischemia progresses. c-Jun N-terminal kinase-1 (JNK-1) is a stress-regulated kinase that is activated by reactive oxygen and thought to promote injury during severe acute myocardial infarction. Because some reports suggest that JNK-1 can also be protective, we hypothesized that the function of JNK-1 depends on the metabolic state of the heart at the time of reperfusion, a condition that changes progressively with duration of ischemia. Mice treated with JNK-1 inhibitors or transgenic mice wherein the JNK-1 gene was ablated were subjected to 5 or 20 min of ischemia followed by reperfusion. When JNK-1 was inactive, ischemia of only 5 min duration caused massive apoptosis, infarction, and negative remodeling that was equivalent to or greater than extended ischemia. Conversely, when ischemia was extended JNK-1 inactivation was protective. Mechanisms of the JNK-1 switch in function were investigated in vivo and in cultured cardiac myocytes. In vitro there was a comparable switch in the function of JNK-1 from protective when ATP levels were maintained during hypoxia to injurious when reoxygenation followed glucose and ATP depletion. Both apoptotic and necrotic death pathways were affected and responded reciprocally to JNK-1 inhibitors. JNK-1 differentially regulated Akt phosphorylation of the regulatory sites Ser-473 and Thr-450 and the catalytic Thr-308 site in vivo. The studies define a novel role for JNK-1 as a conditional survival kinase that protects the heart against brief but not protracted ischemia.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Wei
authors.forename: Weiwen
authors.initials: W
authors.lastname: Wang
authors.forename: Ines
authors.initials: I
authors.lastname: Chopra
authors.forename: Hui Fang
authors.initials: HF
authors.lastname: Li
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dougherty
authors.forename: Jennipher
authors.initials: J
authors.lastname: Adi
authors.forename: Nikhil
authors.initials: N
authors.lastname: Adi
authors.forename: Huilan
authors.initials: H
authors.lastname: Wang
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D002384:Catalysis; D005947:Glucose / Q000737:chemistry; D007511:Ischemia / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry
chemical_list: D013912:Threonine; D012694:Serine; D000255:Adenosine Triphosphate; D048055:Mitogen-Activated Protein Kinase 8; D005947:Glucose