title: Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3.
abstract: Apoptosis is a key pathologic feature in acute lung injury. Animal studies have demonstrated that pathways regulating apoptosis are necessary in the development of acute lung injury, and that activation of p38 mitogen-activated protein kinase (MAPK) is linked to the initiation of the apoptotic cascade. In this study, we assessed the role of the MAPK-activated protein kinase (MK) 2, one of p38 MAPK's immediate downstream effectors, in the development of apoptosis in an animal model of LPS-induced pulmonary vascular permeability. Our results indicate that wild-type (WT) mice exposed to LPS demonstrate increased apoptosis, as evidenced by cleavage of caspase 3 and poly (ADP-ribose) polymerase 1 and increased deoxynucleotidyl transferase-mediated dUDP nick-end labeling staining, which is accompanied by increases in markers of vascular permeability. In contrast, MK2(-/-) mice are protected from pulmonary vascular permeability and apoptosis in response to LPS. Although there was no difference in activation of caspase 3 in MK2(-/-) compared with WT mice, interestingly, cleaved caspase 3 translocated to the nucleus in WT mice while it remained in the cytosol of MK2(-/-) mice in response to LPS. In separate experiments, LPS-induced apoptosis in human lung microvascular endothelial cells was also associated with nuclear translocation of cleaved caspase 3 and apoptosis, which were both prevented by MK2 silencing. In conclusion, our data suggest that MK2 plays a critical role in the development of apoptosis and pulmonary vascular permeability, and its effects on apoptosis are in part related to its ability to regulate nuclear translocation of cleaved caspase 3.
authors.affiliation: 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Damarla
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Parniani
authors.forename: Laura
authors.initials: L
authors.lastname: Johnston
authors.forename: Hasina
authors.initials: H
authors.lastname: Maredia
authors.forename: Leonid
authors.initials: L
authors.lastname: Serebreni
authors.forename: Omar
authors.initials: O
authors.lastname: Hamdan
authors.forename: Venkataramana K
authors.initials: VK
authors.lastname: Sidhaye
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Shimoda
authors.forename: Allen C
authors.initials: AC
authors.lastname: Myers
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Eric P
authors.initials: EP
authors.lastname: Schmidt
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Machamer
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Madhavi J
authors.initials: MJ
authors.lastname: Rane
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kolb
authors.forename: Bo S
authors.initials: BS
authors.lastname: Kim
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Damico
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002199:Capillary Permeability; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D053148:Caspase 3; D047908:Intracellular Signaling Peptides and Proteins; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2