TY - JOUR
T1 - Over-expression of MAP kinase phosphatase-2 enhances adhesion molecule expression and protects against apoptosis in human endothelial cells
AU - Al-Mutairi, Mashael
AU - Al-Harthi, Sameer
AU - Cadalbert, Laurence
AU - Plevin, Robin
PY - 2010
Y1 - 2010
N2 - In this study we used adenovirus infection to overexpress
the dual specific phosphatase, MAP kinase phosphatase-2 (MKP-2), in human umbilical vein endothelial cells and examined inflammatory protein expression and
apoptosis, two key features of endothelial dysfunction in disease. We generated an adenoviral version of MKP-2
(Adv.MKP-2) and infected HUVECs for 40 h. TNF! stimulated MAP kinase phosphorylation and protein expression was measured by Western blotting. Cellular apoptosis was assayed by FACS. Infection with Adv.MKP-2 selectively abolished TNF!-mediated JNK activation and had little effect upon ERK or p38 MAP kinase. Adv.MKP-2 abrogated
COX-2 expression whilst induction of the endothelial cell adhesion molecules ICAM and VCAM, two NF"B-dependent proteins, were not affected. However, when ICAM and VCAM expression was partly reduced by blockage of the NF"B pathway Adv.MKP-2 was able to reverse this inhibition. This correlated with enhanced TNF!-induced I"B! loss, a marker of NF"B activation. TNF! in combination with NF"B blockade also increased HUVEC apoptosis; this was significantly reversed by Adv.MKP-2. Protein markers of cellular damage and apoptosis, H2AX phosphorylation and caspase-3 cleavage, were also reversed by MKP-2 overexpression.
AB - In this study we used adenovirus infection to overexpress
the dual specific phosphatase, MAP kinase phosphatase-2 (MKP-2), in human umbilical vein endothelial cells and examined inflammatory protein expression and
apoptosis, two key features of endothelial dysfunction in disease. We generated an adenoviral version of MKP-2
(Adv.MKP-2) and infected HUVECs for 40 h. TNF! stimulated MAP kinase phosphorylation and protein expression was measured by Western blotting. Cellular apoptosis was assayed by FACS. Infection with Adv.MKP-2 selectively abolished TNF!-mediated JNK activation and had little effect upon ERK or p38 MAP kinase. Adv.MKP-2 abrogated
COX-2 expression whilst induction of the endothelial cell adhesion molecules ICAM and VCAM, two NF"B-dependent proteins, were not affected. However, when ICAM and VCAM expression was partly reduced by blockage of the NF"B pathway Adv.MKP-2 was able to reverse this inhibition. This correlated with enhanced TNF!-induced I"B! loss, a marker of NF"B activation. TNF! in combination with NF"B blockade also increased HUVEC apoptosis; this was significantly reversed by Adv.MKP-2. Protein markers of cellular damage and apoptosis, H2AX phosphorylation and caspase-3 cleavage, were also reversed by MKP-2 overexpression.
KW - map kinase phosphatase-2
KW - endothelial cell dysfunction
KW - caspase
KW - jnk
KW - apoptosis
UR - http://www.scopus.com/inward/record.url?scp=77957224853&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2010.00952.x
DO - 10.1111/j.1476-5381.2010.00952.x
M3 - Article
SN - 0007-1188
VL - 161
SP - 782
EP - 798
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4
ER -