Runx2 Represses Myocardin-Mediated Differentiation and Facilitates Osteogenic Conversion of Vascular Smooth Muscle Cells

Abstract

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.

ACKNOWLEDGMENTS

We are grateful to Gerard Karsenty and Yoshiaki Ito for critical reagents. We thank Yoshiko Nonaka, Miyuki Nomura, and Yukiyo Tosaka for technical assistance.

This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sport and Culture of Japan; a grant from the Japan Cardiovascular Foundation (to M.K.) and Kowa Pharmaceutical; and a Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology, 2007 (to T.T.).