title: Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo.
abstract: The c-Jun NH2-terminal kinase (JNK) branch of the mitogen-activated protein kinase signaling cascade has been implicated in the regulation of apoptosis in a variety of mammalian cell types. In the heart, disagreement persists concerning the role that JNKs may play in regulating apoptosis, since both pro- and antiapoptotic regulatory functions have been reported in cultured cardiomyocytes. Here we report the first analysis of cardiomyocyte cell death due to JNK inhibition or activation in vivo using genetically modified mice. Three separate mouse models with selective JNK inhibition were assessed for ventricular damage and apoptosis levels following ischemia-reperfusion injury. jnk1-/-, jnk2-/-, and transgenic mice expressing dominant negative JNK1/2 within the heart were each shown to have less JNK activity in the heart and less injury and cellular apoptosis in vivo following ischemia-reperfusion injury. To potentially address the reciprocal gain-of-function phenotype associated with sustained JNK activation, transgenic mice were generated that express MKK7 in the heart. These transgenic mice displayed elevated cardiac c-Jun kinase activity but, ironically, were also significantly protected from ischemia-reperfusion. Mechanistically, JNK-inhibited mice showed increased phosphorylation of the proapoptotic factor Bad at position 112, whereas MKK7 transgenic mice showed decreased phosphorylation of this site. Collectively, these results underscore the complexity associated with JNK signaling in regulating apoptosis, such that sustained inhibition or activation both elicit cellular protection in vivo, although probably through different mechanisms.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kaiser
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Liang
authors.forename: Orlando
authors.initials: O
authors.lastname: Bueno
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
authors.forename: Troy
authors.initials: T
authors.lastname: Lackey
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Hewett
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D048429:Cell Size; D004452:Echocardiography; D006321:Heart / Q000033:anatomy & histology; D020287:In Situ Nick-End Labeling; D048688:MAP Kinase Kinase 7 / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics* / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics* / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D015427:Reperfusion Injury; D012694:Serine / Q000737:chemistry; D013997:Time Factors
chemical_list: D012694:Serine; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse