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


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.
Cheng
Jizhong
J
Department of Medicine, Baylor College of Medicine, Houston, Tex, USA.
Wang
Ying
Y
Ma
Yewei
Y
Chan
Bonita Tak-yee
BT
Yang
Min
M
Liang
Anlin
A
Zhang
Liping
L
Li
Huihua
H
Du
Jie
J
D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D013997:Time Factors; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D014680:Veins / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D000099184:Serum-Glucocorticoid Regulated Kinases
D050760:Cyclin-Dependent Kinase Inhibitor p27; D017874:Immediate-Early Proteins; D048369:MAP Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D015534:Trans-Activators; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases; C493961:Cdkn1b protein, mouse; C504923:Crtc2 protein, mouse; C482127:Map2k1 protein, mouse