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 Sidhaye, Larissa Shimoda, Allen C. Myers, Michael T. Crow, Eric P. Schmidt, Carolyn E Machamer, Matthias Gaestel, Madhavi J. Rane, Todd Matthew Kolb, Bo Soo Kim, Rachel L Damico, Paul M Hassoun

Research output: Contribution to journalArticle

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 - 2014

Fingerprint

Capillary Permeability
Mitogen-Activated Protein Kinases
Caspase 3
Protein Kinases
Apoptosis
Lung
Acute Lung Injury
p38 Mitogen-Activated Protein Kinases
Animals
Chemical activation
DNA Nucleotidylexotransferase
Poly(ADP-ribose) Polymerases
Endothelial cells
Cytosol
Labeling
Endothelial Cells
Animal Models
Staining and Labeling

Keywords

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

ASJC Scopus subject areas

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

Cite this

Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3. / Damarla, Mahendra; Parniani, Ahmad R.; Johnston, Laura; Maredia, Hasina; Serebreni, Leonid; Hamdan, Omar; Sidhaye, Venkataramana; Shimoda, Larissa; Myers, Allen C.; Crow, Michael T.; Schmidt, Eric P.; Machamer, Carolyn E; Gaestel, Matthias; Rane, Madhavi J.; Kolb, Todd Matthew; Kim, Bo Soo; Damico, Rachel L; Hassoun, Paul M.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 50, No. 5, 2014, p. 932-941.

Research output: Contribution to journalArticle

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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.",
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T1 - Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3

AU - Damarla, Mahendra

AU - Parniani, Ahmad R.

AU - Johnston, Laura

AU - Maredia, Hasina

AU - Serebreni, Leonid

AU - Hamdan, Omar

AU - Sidhaye, Venkataramana

AU - Shimoda, Larissa

AU - Myers, Allen C.

AU - Crow, Michael T.

AU - Schmidt, Eric P.

AU - Machamer, Carolyn E

AU - Gaestel, Matthias

AU - Rane, Madhavi J.

AU - Kolb, Todd Matthew

AU - Kim, Bo Soo

AU - Damico, Rachel L

AU - Hassoun, Paul M

PY - 2014

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N2 - 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.

AB - 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.

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