Open AccessRunx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells
Author(s) -
Toru Tanaka,
Hiroko Sato,
Hiroshi Doi,
Chisato Yoshida,
Tomohiro Shimizu,
Hiroki Matsui,
Miki Yamazaki,
Hideo Akiyama,
Keiko Kawai-Kowase,
Tatsuya Iso,
Toshihisa Komori,
M. Arai,
Masahiko Kurabayashi
Publication year - 2008
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01771-07
Subject(s) - myocardin , runx2 , biology , serum response factor , corepressor , microbiology and biotechnology , coactivator , transcription factor , small interfering rna , gene expression , cellular differentiation , psychological repression , gene , transfection , genetics
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.