Stent implantation activates Akt in the vessel wall: role of mechanical stretch in vascular smooth muscle cells.
OBJECTIVE
The long-term efficacy of stent implantation is affected by in-stent restenosis (ISR). Multiple factors can contribute to ISR, and the underlying mechanism remains elusive. We investigated the possible role of mechanical stretch and the associated molecular signaling in ISR.


RESULTS
Stent implantation in rat abdominal aortas induced neointima formation. Immunohistochemical studies revealed the activation of Akt in the media and neointima of the stented vessels. Western blotting showed increased phosphorylation of Akt at both Thr308 and Ser473 and phosphorylation of GSK-3beta in the stented vessels. A stretch device applying static equibiaxial stretch on cultured vascular smooth muscle cells was used to delineate the molecular mechanism underlying the stretch activation of Akt. Static mechanical stretch induced the sustained activation of Akt and its upstream phosphoinositide 3-kinase (PI3K) and the phosphorylation of GSK-3beta, its downstream effector in vascular smooth muscle cells. LY294002, a PI3K inhibitor, and N-acetylcysteine, a scavenger of reactive oxygen species, inhibited the stretch activation of Akt. Furthermore, N-acetylcysteine and wortmannin, another PI3K inhibitor, reduced the neointima formation after stent implantation.


CONCLUSIONS
Mechanical stretch of the vascular wall during stent deployment may contribute to ISR by activating the Akt pathway.
Zhou
Rui-Hai
RH
Division of Biomedical Sciences, University of California, Riverside, Riverside, Calif 92521-0121, USA.
Lee
Tzong-Shyuan
TS
Tsou
Tsui-Chun
TC
Rannou
François
F
Li
Yi-Shuan
YS
Chien
Shu
S
Shyy
John Y-J
JY
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015607:Stents; D013314:Stress, Mechanical
D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt