Abstract
We have previously shown that thrombin induces endothelial cell barrier dysfunction via cytoskeleton activation and contraction and have determined the important role of endothelial cell myosin light chain kinase (MLCK) in this process. In the present study we explored p38 MAP kinase as a potentially important enzyme in thrombin-mediated endothelial cell contractile response and permeability. Thrombin induces significant p38 MAP kinase activation in a time-dependent manner with maximal effect at 30 min, which correlates with increased phosphorylation of actin- and myosin-binding protein, caldesmon. Both SB-203580 and dominant negative p38 adenoviral vector significantly attenuated thrombin-induced declines in transendothelial electrical resistance. Consistent with these data SB-203580 decreased actin stress fiber formation produced by thrombin in endothelium. In addition, dominant negative p38 had no effect on thrombin-induced myosin light chain diphosphorylation. Thrombin-induced total and site-specific caldesmon phosphorylation (Ser789) as well as dissociation of caldesmon-myosin complex were attenuated by SB-203580 pretreatment. These results suggest the involvement of p38 MAP kinase activities and caldesmon phosphorylation in the MLCK-independent regulation of thrombin-induced endothelial cell permeability.
| Original language | English (US) |
|---|---|
| Pages (from-to) | L911-L918 |
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 287 |
| Issue number | 5 31-5 |
| DOIs | |
| State | Published - Nov 1 2004 |
| Externally published | Yes |
Fingerprint
Keywords
- Caldesmon
- Thrombin
- Transendothelial electrical resistance
- p38 mitogen-activated protein kinase
ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Physiology (medical)
- Cell Biology
Cite this
p38 MAP kinase-dependent regulation of endothelial cell permeability. / Borbiev, Talaibek; Birukova, Anna; Liu, Feng; Nurmukhambetova, Saule; Gerthoffer, William T.; Garcia, Joe G.N.; Verin, Alexander Dmitriyevich.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 287, No. 5 31-5, 01.11.2004, p. L911-L918.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - p38 MAP kinase-dependent regulation of endothelial cell permeability
AU - Borbiev, Talaibek
AU - Birukova, Anna
AU - Liu, Feng
AU - Nurmukhambetova, Saule
AU - Gerthoffer, William T.
AU - Garcia, Joe G.N.
AU - Verin, Alexander Dmitriyevich
PY - 2004/11/1
Y1 - 2004/11/1
N2 - We have previously shown that thrombin induces endothelial cell barrier dysfunction via cytoskeleton activation and contraction and have determined the important role of endothelial cell myosin light chain kinase (MLCK) in this process. In the present study we explored p38 MAP kinase as a potentially important enzyme in thrombin-mediated endothelial cell contractile response and permeability. Thrombin induces significant p38 MAP kinase activation in a time-dependent manner with maximal effect at 30 min, which correlates with increased phosphorylation of actin- and myosin-binding protein, caldesmon. Both SB-203580 and dominant negative p38 adenoviral vector significantly attenuated thrombin-induced declines in transendothelial electrical resistance. Consistent with these data SB-203580 decreased actin stress fiber formation produced by thrombin in endothelium. In addition, dominant negative p38 had no effect on thrombin-induced myosin light chain diphosphorylation. Thrombin-induced total and site-specific caldesmon phosphorylation (Ser789) as well as dissociation of caldesmon-myosin complex were attenuated by SB-203580 pretreatment. These results suggest the involvement of p38 MAP kinase activities and caldesmon phosphorylation in the MLCK-independent regulation of thrombin-induced endothelial cell permeability.
AB - We have previously shown that thrombin induces endothelial cell barrier dysfunction via cytoskeleton activation and contraction and have determined the important role of endothelial cell myosin light chain kinase (MLCK) in this process. In the present study we explored p38 MAP kinase as a potentially important enzyme in thrombin-mediated endothelial cell contractile response and permeability. Thrombin induces significant p38 MAP kinase activation in a time-dependent manner with maximal effect at 30 min, which correlates with increased phosphorylation of actin- and myosin-binding protein, caldesmon. Both SB-203580 and dominant negative p38 adenoviral vector significantly attenuated thrombin-induced declines in transendothelial electrical resistance. Consistent with these data SB-203580 decreased actin stress fiber formation produced by thrombin in endothelium. In addition, dominant negative p38 had no effect on thrombin-induced myosin light chain diphosphorylation. Thrombin-induced total and site-specific caldesmon phosphorylation (Ser789) as well as dissociation of caldesmon-myosin complex were attenuated by SB-203580 pretreatment. These results suggest the involvement of p38 MAP kinase activities and caldesmon phosphorylation in the MLCK-independent regulation of thrombin-induced endothelial cell permeability.
KW - Caldesmon
KW - Thrombin
KW - Transendothelial electrical resistance
KW - p38 mitogen-activated protein kinase
UR - http://www.scopus.com/inward/record.url?scp=6344254520&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=6344254520&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00372.2003
DO - 10.1152/ajplung.00372.2003
M3 - Article
C2 - 15475493
AN - SCOPUS:6344254520
VL - 287
SP - L911-L918
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 5 31-5
ER -