The Mechanical Stress–Activated Serum-, Glucocorticoid-Regulated Kinase 1 Contributes to Neointima Formation in Vein Grafts

• Published in: Circulation research Vol. 107; no. 10; pp. 1265 - 1274
• Main Authors: Cheng, Jizhong, Wang, Ying, Ma, Yewei, Chan, Bonita Tak-yee, Yang, Min, Liang, Anlin, Zhang, Liping, Li, Huihua, Du, Jie
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 12.11.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Biological and medical sciences; Carotid Artery Injuries - enzymology; Carotid Artery Injuries - pathology; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Disease Models, Animal; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling - methods; Gene Expression Regulation, Enzymologic; Immediate-Early Proteins - deficiency; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Male; MAP Kinase Kinase 1 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Transport; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; Stress, Mechanical; Time Factors; Tissue Culture Techniques; Trans-Activators - metabolism; Transcription Factors; Transfection; Tunica Intima - drug effects; Tunica Intima - enzymology; Tunica Intima - pathology; Veins - enzymology; Veins - pathology; Veins - transplantation; Vertebrates: cardiovascular system; neointima formation; Sirolimus; Enzyme; Transferases; Mitogen-activated protein kinase; Lactone; mechanical stretch; Macrolide; Glucocorticoid; Macrocycle; Vertebrata; Mammalia; Mechanical stress; Kinase; Blood vessel; serum-, glucocorticoid-regulated kinase-1; mammalian target of rapamycin complex; Graft; Protein synthesis inhibitor; Circulatory system; Vein; Formation; mTORC
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.222588

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, whereas knockout of SGK-1 attenuated this effect of mechanical stretch on p27. 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 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.