Mechanisms of endothelial cell protection by blockade of the JAK2 pathway
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2006-10-11
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American Physiological Society
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Inhibition of the JAK2/
STAT pathway has been implicated recently in cytoprotective mech-
anisms in both vascular smooth muscle cells and astrocytes. The
advent of JAK2-specific inhibitors provides a practical tool for the
study of this pathway in different cellular types. An interest in finding
methods to improve endothelial cell (EC) resistance to injury led us to
examine the effect of JAK2/STAT inhibition on EC protection.
Furthermore, the signaling pathways involved in JAK2/STAT inhibi-
tion-related actions were examined. Our results reveal, for the first
time, that blockade of JAK2 with the tyrosine kinase inhibitor AG490
strongly protects cultured EC against cell detachment-dependent
death and serum deprivation and increases reseeding efficiency. Con-
firmation of the specificity of the effects of JAK2 inhibition was
attained by finding protective effects on transfection with a dominant
negative JAK2. Furthermore, AG490 blocked serum deprivation-
induced phosphorylation of JAK2. In terms of mechanism, treatment
with AG490 induces several relevant responses, both in monolayer
and detached cells. These mechanisms include the following: 1)
Increase and nuclear translocation of the active, dephosphorylated
form of -catenin. In functional terms, this translocation is transcrip-
tionally active, and its protective effect is further supported by the
stimulation of EC cytoprotection by transfectionally induced excess of
-catenin. 2) Increase of platelet endothelial cell adhesion molecule
(PECAM)/CD31 levels. 3) Increase in total and phosphorylated AKT.
4) Increase in phosphorylated glycogen synthase kinase (GSK)3 / .
The present findings imply potential practical applications of JAK2
inhibition on EC. These applications affect not only EC in the
monolayer but also circulating detached cells and involve mechanistic
interactions not previously described.
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Mechanisms of endothelial cell protection by blockade of the JAK2 pathway Fernando Neria, Carlos Caramelo, Héctor Peinado, Francisco R. González-Pacheco, Juan JP. Deudero, Alain J. de Solis, Ruth Fernández-Sánchez, Silvia Peñate, Amparo Cano, and Mª Ángeles Castilla American Journal of Physiology-Cell Physiology 2007 292:3, C1123-C1131