Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling

Hyun Byon Chang, Amjad Javed, Qun Dai, John C. Kappes, Thomas Clemens, Victor M. Darley-Usmar, Jay M. McDonald, Yabing Chen

Research output: Contribution to journalArticle

Abstract

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis including the formation of lipid laden macrophages and the development of inflammation. However, oxidative stress-induced molecular signaling that regulates the development of vascular calcification has not been investigated in depth. Osteogenic differentiation of vascular smooth muscle cells (VSMC) is critical in the development of calcification in atherosclerotic lesions. An important contributor to oxidative stress in atherosclerotic lesions is the formation of hydrogen peroxide from diverse sources in vascular cells. In this study we defined molecular signaling that is operative in the H 2O2-induced VSMC calcification. We found that H 2O2 promotes a phenotypic switch of VSMC from contractile to osteogenic phenotype. This response was associated with an increased expression and transactivity of Runx2, a key transcription factor for osteogenic differentiation. The essential role of Runx2 in oxidative stress-induced VSMC calcification was further confirmed by Runx2 depletion and overexpression. Inhibition of Runx2 using short hairpin RNA blocked VSMC calcification, and adenovirus-mediated overexpression of Runx2 alone induced VSMC calcification. Inhibition of H2O2-activated AKT signaling blocked VSMC calcification and Runx2 induction concurrently. This blockage did not cause VSMC apoptosis. Taken together, our data demonstrate a critical role for AKT-mediated induction of Runx2 in oxidative stress-induced VSMC calcification.

Original languageEnglish (US)
Pages (from-to)15319-15327
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number22
DOIs
StatePublished - May 30 2008
Externally publishedYes

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Calcification (biochemistry)
Vascular Calcification
Oxidative stress
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Oxidative Stress
Transcription Factors
Modulation
Macrophages
Adenoviridae
Hydrogen Peroxide
Small Interfering RNA
Blood Vessels
Atherosclerosis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. / Chang, Hyun Byon; Javed, Amjad; Dai, Qun; Kappes, John C.; Clemens, Thomas; Darley-Usmar, Victor M.; McDonald, Jay M.; Chen, Yabing.

In: Journal of Biological Chemistry, Vol. 283, No. 22, 30.05.2008, p. 15319-15327.

Research output: Contribution to journalArticle

Chang, Hyun Byon ; Javed, Amjad ; Dai, Qun ; Kappes, John C. ; Clemens, Thomas ; Darley-Usmar, Victor M. ; McDonald, Jay M. ; Chen, Yabing. / Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 22. pp. 15319-15327.
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