title: MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo.
abstract: BACKGROUND
  Myocardial infarction causes a rapid and largely irreversible loss of cardiac myocytes that can lead to sudden death, ventricular dilation, and heart failure. Members of the mitogen-activated protein kinase (MAPK) signaling cascade have been implicated as important effectors of cardiac myocyte cell death in response to diverse stimuli, including ischemia-reperfusion injury. Specifically, activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) has been associated with cardioprotection, likely through antagonism of apoptotic regulatory pathways.
  
  
  RESULTS
  To establish a causal relationship between ERK1/2 signaling and cardioprotection, we analyzed Erk1 nullizygous gene-targeted mice, Erk2 heterozygous gene-targeted mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart. Although MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury, Erk2+/- gene-targeted mice showed enhanced infarction areas, DNA laddering, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling (TUNEL) compared with littermate controls. In contrast, enhanced MEK1-ERK1/2 signaling protected hearts from DNA laddering, TUNEL, and preserved hemodynamic function assessed by pressure-volume loop recordings after ischemia-reperfusion injury.
  
  
  CONCLUSIONS
  These data are the first to demonstrate that ERK2 signaling is required to protect the myocardium from ischemia-reperfusion injury in vivo.
authors.affiliation: Department of Cardiology, Maastricht University, and Heart Lung Center Utrecht, Maastricht and Utrecht, Netherlands.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lips
authors.forename: Orlando F
authors.initials: OF
authors.lastname: Bueno
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Wilkins
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Purcell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kaiser
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Laure
authors.initials: L
authors.lastname: Voisin
authors.forename: Marc K
authors.initials: MK
authors.lastname: Saba-El-Leil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D017209:Apoptosis; D006439:Hemodynamics; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases