Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3

Mahendra Damarla, Ahmad R. Parniani, Laura Johnston, Hasina Maredia, Leonid Serebreni, Omar Hamdan, Venkataramana K. Sidhaye, Larissa A. Shimoda, Allen C. Myers, Michael T. Crow, Eric P. Schmidt, Carolyn E. Machamer, Matthias Gaestel, Madhavi J. Rane, Todd M. Kolb, Bo S. Kim, Rachel L. Damico, Paul M. Hassoun

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 withWT mice, interestingly, cleaved caspase 3 translocated to the nucleus inWT 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 byMK2 silencing. In conclusion, our data suggest thatMK2 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.

Original languageEnglish (US)
Pages (from-to)932-941
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume50
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Apoptosis
  • Caspase 3
  • Kinases
  • Lung injury
  • Nuclear translocation

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3'. Together they form a unique fingerprint.

Cite this