Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling.
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 H2O2-induced VSMC calcification. We found that H2O2 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.
Byon
Chang Hyun
CH
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Javed
Amjad
A
Dai
Qun
Q
Kappes
John C
JC
Clemens
Thomas L
TL
Darley-Usmar
Victor M
VM
McDonald
Jay M
JM
Chen
Yabing
Y
D000256:Adenoviridae; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt