Bone morphogenetic protein-2 activates NADPH oxidase to increase endoplasmic reticulum stress and human coronary artery smooth muscle cell calcification

Author(s)

Liberman, Marcel ^[1] ; Johnson, Rebecca C. ^[1] ; Handy, Diane E. ^[1] ; Loscalzo, Joseph ^[1] ; Leopold, Jane A. ^[2]

Affiliation

^[1] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[2] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 - USA

• Document type: Journal article
• Source: Biochemical and Biophysical Research Communications; v. 413, n. 3, p. 436-441, SEP 30 2011.
• Web of Science Citations: 53

Abstract

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. (AU)