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Circ Res. 2010 Oct 15;107(8):984-91. doi: 10.1161/CIRCRESAHA.110.222794. Epub 2010 Aug 19.

Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension.

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  • 1School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. jack_wong@cuhk.edu.hk

Abstract

RATIONALE:

Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive.

OBJECTIVE:

To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress-dependent upregulation of cyclooxygenase (COX)-2.

METHODS AND RESULTS:

Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1(-/-) or COX-2(-/-) mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4-treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction.

CONCLUSIONS:

We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.

PMID:
20724703
[PubMed - indexed for MEDLINE]
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