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The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts.

Abstract：

RATIONALE:Mechanical stress plays an important role in proliferation of venous smooth muscle cells (SMCs) in neointima, a process of formation that contributes to failure of vein grafts. However, it is unknown what intracellular growth signal leads to proliferation of venous SMCs. OBJECTIVE:The objective of this study is to identify mechanisms of mechanical stretch on neointima formation. METHODS AND RESULTS:By a microarray analysis, we found that mechanical cyclic stretch (15% elongation) stimulated the transcription of SGK-1 (serum-, glucocorticoid-regulated kinase-1). Mechanical stretch-induced SGK-1 mRNA expression was blocked by actinomycin D. The mechanism for the SGK-1 expression involved MEK1 but not p38 or JNK signaling pathway. SGK-1 activation in response to stretch is blocked by insulin-like growth factor (IGF)-1 receptor inhibitor and mammalian target of rapamycin complex (mTORC)2 inhibitor (Ku-0063794) but not mTORC1 inhibitor (rapamycin). Mechanical stretch-induced bromodeoxyuridine incorporation was reduced by 83.5% in venous SMCs isolated from SGK-1 knockout mice. In contrast, inhibition of Akt, another downstream signal of PI3K resulted in only partial inhibition of mechanical stretch-induced proliferation of venous SMCs. Mechanical stretch also induced phosphorylation and nuclear exportation of p27(kip1), whereas knockout of SGK-1 attenuated this effect of mechanical stretch on p27(kip1). In vivo, we found that placement of a vein graft into artery increased SGK-1 expression. Knockout of SGK-1 effectively prevented neointima formation in vein graft. There is significant lower level of p27(kip1) located in the nucleus of neointima cells in SGK-1 knockout mice compared with that of wild-type vein graft. In addition, we also found that wire injury of artery or growth factors in vitro increased expression of SGK-1. CONCLUSIONS:These results suggest that SGK-1 is an injury-responsive kinase that could mediate mechanical stretch-induced proliferation of vascular cells in vein graft, leading to neointima formation.

journal_name

Circ Res

journal_title

Circulation research

authors

Cheng J,Wang Y,Ma Y,Chan BT,Yang M,Liang A,Zhang L,Li H,Du J

doi

10.1161/CIRCRESAHA.110.222588

subject

Has Abstract

pub_date

2010-11-12 00:00:00

pages

1265-74

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.110.222588

journal_volume

107

pub_type

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The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts.