TR3 nuclear orphan receptor prevents cyclic stretch-induced proliferation of venous smooth muscle cells.
In coronary artery bypass surgery, the patency of arterial grafts is higher than that of venous grafts because of vein-graft disease, which involves excessive proliferation of venous smooth muscle cells (SMCs) and subsequent accelerated atherosclerosis. We studied the function of TR3 nuclear orphan receptor (TR3) in the early response of SMCs to mechanical strain, a major initiator of vein-graft disease. We demonstrate that TR3 expression is induced in human saphenous vein segments exposed ex vivo to whole-blood perfusion under arterial pressure. Cultured venous SMCs challenged by cyclic stretch displayed TR3 induction and enhanced DNA synthesis, whereas SMCs derived from the internal mammary artery remained quiescent. Small-interfering RNA-mediated knockdown of TR3 and adenovirus-mediated overexpression of TR3 in venous SMCs enhanced and abolished stretch-induced DNA synthesis, respectively. Accordingly, in organ cultures of wild-type murine vessel segments exposed to cyclic stretch, p27(Kip1) was down-regulated, whereas expression of this cell cycle inhibitor was unaffected by cyclic stretch in TR3-transgenic vessels, concordant with a lower proliferative response. Finally, stretch-mediated proliferation was inhibited by 6-mercaptopurine, an agonist of TR3. In conclusion, TR3 represents inhibitory mechanisms to restrict venous SMC proliferation and may contribute to prevention of vein-graft disease.
de Waard
Vivian
V
Department of Medical Biochemistry, Academic Medical Center, K1-116, Meibergdreef 15, 1105 AZ Amsterdam. c.j.devries@amc.uva.nl.
Arkenbout
E Karin
EK
Vos
Mariska
M
Mocking
Astrid I M
AI
Niessen
Hans W M
HW
Stooker
Wim
W
de Mol
Bas A J M
BA
Quax
Paul H A
PH
Bakker
Erik N T P
EN
VanBavel
Ed
E
Pannekoek
Hans
H
de Vries
Carlie J M
CJ
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering / Q000378:metabolism; D011987:Receptors, Steroid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000502:physiology*
C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D050760:Cyclin-Dependent Kinase Inhibitor p27