Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling.
OBJECTIVE
Vascular remodeling because of smooth muscle cell (SMC) proliferation is a common process occurring in several vascular diseases, such as atherosclerosis, aortic aneurysm, post-transplant vasculopathy, restenosis after angioplasty, etc. The molecular mechanism underlying SMC proliferation, however, is not completely understood. The objective of this study is to determine the role and mechanism of Janus kinase 3 (JAK3) in vascular remodeling and SMC proliferation.


APPROACH AND RESULTS
Platelet-derived growth factor-BB, an SMC mitogen, induces JAK3 expression and phosphorylation while stimulating SMC proliferation. Janex-1, a specific inhibitor of JAK3, or knockdown of JAK3 by short hairpin RNA, inhibits the SMC proliferation. Conversely, ectopic expression of JAK3 promotes SMC proliferation. Mechanistically, JAK3 promotes the phosphorylation of signal transducer and activator of transcription 3 and c-Jun N-terminal kinase in SMC, 2 signaling pathways known to be critical for SMC proliferation and vascular remodeling. Blockade of these 2 signaling pathways by their inhibitors impeded the JAK3-mediated SMC proliferation. In vivo, knockdown of JAK3 attenuates injury-induced neointima formation with attenuated neointimal SMC proliferation. Knockdown of JAK3 also induces neointimal SMC apoptosis in rat carotid artery balloon injury model.


CONCLUSIONS
Our results demonstrate that JAK3 mediates SMC proliferation and survival during injury-induced vascular remodeling, which provides a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.
['Wang|Yung-Chun|YC|', 'Cui|Xiao-Bing|XB|', 'Chuang|Ya-Hui|YH|', 'Chen|Shi-You|SY|']
D000818:Animals D017209:Apoptosis D000077214:Becaplermin D002339:Carotid Arteries D020212:Carotid Artery Injuries D049109:Cell Proliferation D002478:Cells, Cultured D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D053616:Janus Kinase 3 D020928:Mitogen-Activated Protein Kinases D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D058426:Neointima D010766:Phosphorylation D047428:Protein Kinase Inhibitors D020574:Proto-Oncogene Proteins c-sis D011799:Quinazolines D034622:RNA Interference D051381:Rats D050796:STAT3 Transcription Factor D015398:Signal Transduction D013997:Time Factors D014162:Transfection D066253:Vascular Remodeling
Janus kinase 3 smooth muscle proliferation vascular remodeling apoptosis interleukin