title: TR3 nuclear orphan receptor prevents cyclic stretch-induced proliferation of venous smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, K1-116, Meibergdreef 15, 1105 AZ Amsterdam. c.j.devries@amc.uva.nl.
authors.forename: Vivian
authors.initials: V
authors.lastname: de Waard
authors.forename: E Karin
authors.initials: EK
authors.lastname: Arkenbout
authors.forename: Mariska
authors.initials: M
authors.lastname: Vos
authors.forename: Astrid I M
authors.initials: AI
authors.lastname: Mocking
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Wim
authors.initials: W
authors.lastname: Stooker
authors.forename: Bas A J M
authors.initials: BA
authors.lastname: de Mol
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Erik N T P
authors.initials: EN
authors.lastname: Bakker
authors.forename: Ed
authors.initials: E
authors.lastname: VanBavel
authors.forename: Hans
authors.initials: H
authors.lastname: Pannekoek
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: 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*
chemical_list: 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