Runx2 represses myocardin-mediated differentiation and facilitates osteogenic conversion of vascular smooth muscle cells.
Phenotypic plasticity and the switching of vascular smooth muscle cells (SMCs) play a critical role in atherosclerosis. Although Runx2, a key osteogenic transcription factor, is expressed in atherosclerotic plaques, the molecular mechanisms by which Runx2 regulates SMC differentiation remain unclear. Here we demonstrated that Runx2 repressed SMC differentiation induced by myocardin, which acts as a coactivator for serum response factor (SRF). Myocardin-mediated induction of SMC gene expression was enhanced in mouse embryonic fibroblasts derived from Runx2 null mice compared to wild-type mice. Forced expression of Runx2 decreased the expression of SMC genes and promoted osteogenic gene expression, whereas the reduction of Runx2 expression by small interfering RNA enhanced SMC differentiation in human aortic SMCs. Runx2 interacted with SRF and interfered with the formation of the SRF/myocardin ternary complex. Thus, this study provides the first evidence that Runx2 inhibits SRF-dependent transcription, as a corepressor independent of its DNA binding. We propose that Runx2 plays a pivotal role in osteogenic conversion tightly coupled with repression of the SMC phenotype in atherosclerotic lesions.
Tanaka
Toru
T
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-8511, Japan.
Sato
Hiroko
H
Doi
Hiroshi
H
Yoshida
Carolina A
CA
Shimizu
Takehisa
T
Matsui
Hiroki
H
Yamazaki
Miki
M
Akiyama
Hideo
H
Kawai-Kowase
Keiko
K
Iso
Tatsuya
T
Komori
Toshihisa
T
Arai
Masashi
M
Kurabayashi
Masahiko
M
D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000209:etiology; D002454:Cell Differentiation; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D009687:Nuclear Proteins / Q000502:physiology*; D010012:Osteogenesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D026362:Serum Response Factor / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D000099251:Myocardin
D050659:Core Binding Factor Alpha 1 Subunit; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C493716:Runx2 protein, mouse