Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway

Xiao Yu Tian, Lai Hang Yung, Wing Tak Wong, Jian Liu, Fung Ping Leung, Limei Liu, Yangchao Chen, Siu Kai Kong, Kin Ming Kwan, Siu Man Ng, Paul B.S. Lai, Lai Ming Yung, Xiaoqiang Yao, Yu Huang

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

The expression of bone morphogenic protein 4 (BMP4), a new pro-inflammatory marker, is increased by disturbed flow in endothelial cells (ECs). BMP4 stimulates production of reactive oxygen species (ROS) and causes endothelial cell dysfunction. The present study examined BMP4-induced apoptosis in ECs and isolated arteries from rat, mouse, and human, and the signaling pathways mediating BMP4-induced apoptosis. Apoptosis was assessed by flow cytometry to detect Annexin-V positive cells, and terminal deoxynucleotidyl transferase dUTP nick end (TUNEL) labeling. The superoxide production was measured by dihydroethidium fluorescence. BMP4 induced EC apoptosis in human mesenteric arteries, mouse aortic endothelium, rat primary ECs, and human ECs. BMP4-induced EC apoptosis was mediated through ROS production by activation of NADPH oxidase, which led to cleaved caspase-3 expression. BMP4 also induced sequential activation of p38 MAPK and JNK which was upstream of caspase 3 activation. Knockdown of BMP receptor 1A by lentiviral shRNA or NOX4 siRNA transfection inhibited BMP4-induced ROS production, p38 and JNK phosphorylation, and caspase-3 activation in ECs. JNK siRNA inhibited BMP4-induced JNK phosphorylation and caspase-3 activation. The present study delineates that BMP4 causes EC apoptosis through activation of caspase-3 in a ROS/p38MAPK/JNK-dependent signaling cascade.

Original languageEnglish (US)
Pages (from-to)237-244
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume52
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Apoptosis
  • Bone morphogenic protein-4
  • Endothelial cells
  • Mitogen-activated protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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