Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 413, Issue 3, Pages 436-441Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.08.114
Keywords
Bone morphogenetic protein-2; Endoplasmic reticulum stress; Oxidant stress; Vascular calcification; Vascular smooth muscle cells
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Funding
- Conselho Nacional de Pesquisa e Tecnologia
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
- Stanley J. Sarnoff Foundation
- NIH [HL061795, HL048743, HL107192, HL108630, HL070819, HL105301]
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Bone morphogenetic protein-2 (BMP-2) increases oxidant stress and endoplasmic reticulum (ER) stress to stimulate differentiation of osteoblasts; however, the role of these signaling pathways in the transition of smooth muscle cells to a calcifying osteoblast-like phenotype remains incompletely characterized. We, therefore, treated human coronary artery smooth muscle cells (HCSMC) with BMP-2 (100 ng/mL) and found an increase in NADPH oxidase activity and oxidant stress that occurred via activation of the bone morphogenetic protein receptor 2 and Smad 1 signaling. BMP-2-mediated oxidant stress also increased endoplasmic reticulum (ER) stress demonstrated by increased expression of GRP78, phospho-IRE1 alpha, and the transcription factor XBP1. Analysis of a 1 kb segment of the Runx2 promoter revealed an XBP1 binding site; electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that XBP1 bound to the Runx2 promoter at this site in BMP-2-treated HCSMC. Inhibition of oxidant stress or ER stress decreased Runx2 expression, intracellular calcium deposition, and mineralization of BMP-2-treated HCSMC. Thus, in HCSMC, BMP-2 increases oxidant stress and ER stress to increase Runx2 expression and promote vascular smooth muscle cell calcification. (C) 2011 Elsevier Inc. All rights reserved.
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