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

WT Wong, XY Tian, Y Chen, FP Leung, L Liu… - Circulation …, 2010 - Am Heart Assoc
WT Wong, XY Tian, Y Chen, FP Leung, L Liu, HK Lee, CF Ng, A Xu, X Yao, PM Vanhoutte
Circulation research, 2010Am Heart Assoc
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 …
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.
Am Heart Assoc