15-Lipoxygenase promotes chronic hypoxia-induced phenotype changes of PASMCs via positive feedback-loop of BMP4.

Abstract

Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetr-aenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension (PAH). Phenotypical alterations of vascular smooth muscle cells are considered to be an important stage in the development of PAH, whereas the underlying mechanisms and signaling systems are still unclear. Here, we determined the contribution of 15-LO/15-HETE signaling in the hypoxia-induced phenotype changes of pulmonary arterial smooth muscle cells (PASMCs). To accomplish this, cellular and molecular changes in pulmonary vascular remodeling were detected in PAH patients and rats exposed to hypoxia. We found that the hypoxia-induced alterations in PASMCs phenotypes were reversed by the inhibition of 15-LO/15-HETE or inhibition of BMP4/BMPRI. Hypoxia-induced 15-LO1/2 expression in rat PASMCs was significantly abolished by small interfering RNA targeted at BMP4. Meanwhile, BMP4/BMPRI-15-LO/15-HETE had a positive feedback mechanism. Furthermore, ERK and p38MAPK act as the downstream of the 15-LO/15-HETE-BMP4/BMPRI signaling. Our results suggest that chronic hypoxia promotes phenotypical alterations of PASMCs due to the interaction between 15-LO/15-HETE and BMP4/BMPRI. Our study reveals a novel mechanism of hypoxia-induced pulmonary vascular remodeling and suggested new therapeutic strategies for the targeting of 15-LO/15-HETE and BMP4/BMPRI in PAH treatment.

• Authors: Xiufeng Yu, Liuping Wei, Ping Lu, Tingting Shen, Xia Liu, Tingting Li, Bo Zhang, Hao Yu, Daling Zhu
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 230 Issue 7 Pg. 1489-502 (Jul 2015) ISSN: 1097-4652 [Electronic] United States
• PMID: 25521840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• BMP4 protein, human
• Bmp4 protein, rat
• Bone Morphogenetic Protein 4
• Hydroxyeicosatetraenoic Acids
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid
• Arachidonate 15-Lipoxygenase
• Bone Morphogenetic Protein Receptors, Type I
• Oxygen

Topics

• Animals
• Arachidonate 15-Lipoxygenase (genetics, metabolism)
• Bone Morphogenetic Protein 4 (genetics, metabolism)
• Bone Morphogenetic Protein Receptors, Type I (genetics, metabolism)
• Gene Expression Regulation (physiology)
• Humans
• Hydroxyeicosatetraenoic Acids
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (cytology, physiology)
• Oxygen (metabolism)
• Pulmonary Artery (cytology)
• Random Allocation
• Rats