Περίληψη:
Hemodynamic forces, including shear stress and cyclic strain, have been
recognised as important modulators of vascular cell morphology and
function. However, the mechanism by which vascular cells sense and
transduce the extracellular mechanical signals into the cell nucleus has
not yet been clarified. The purpose of our study was to assess the
involvement of the signal transducer and activator of transcription-3
(STAT-3) in the signaling pathway mediating the response of vascular
smooth muscle cells (SMC) to cyclic strain. Embryonic A7r5 SMC derived
from thoracic aortas of DB 1X rats were seeded on flexible collagen
I-coated plates. Cells were subjected to 10% average strain at 60
cycles/min for various time periods. Activation of STAT-3, p38,
extracellular signal -regulated kinase (ERK) 1/2 and Src was assessed by
immunoblotting using phosphospecific antibodies. The interactions
between STAT-3 phosphorylation and p38, ERK 1 /2, phosphatidylinositol-3
(PI3K), mammalian target of rapamycin (mTOR), Janus kinase (JAK) 2 and
Src were evaluated by pretreating the cells with specific inhibitors
including SB202190, PD98059, LY294002, wortmannin, rapamycin, AG490 and
PP I.
Serine phosphorylation of STAT-3 was increased by 2-fold after 15 min of
cyclic strain, while tyrosine phosphorylation was increased by 2.3-fold
after 60 min. Inhibition of ERK 1/2 by PD98059 prevented serine
phosphorylation of STAT-3, whereas inhibition of Src by PP1 prevented
STAT-3 tyrosine phosphorylation. Pretreating the cells with SB202190, a
specific inhibitor of p38, resulted in an increase in basal
phosphorylation of ERK1/2 and a subsequent increase in basal serine
phosphorylation of STAT-3.
In conclusion, both serine and tyrosine phosphorylation of STAT-3 are
involved in the signaling pathway mediating the effects of cyclic strain
on vascular SMC. Serine phosphorylation of STAT-3 is mediated by ERK1/2,
while tyrosine phosphorylation is mediated by Re. A negative feedback
loop was also found between p38 and ERK 1 /2. (c) 2005 Elsevier Ltd. All
rights reserved.
Συγγραφείς:
Kakisis, JD
Pradhan, S
Cordova, A
Liapis, CD
Sumpio, BE
