MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia/15-HETE in pulmonary endothelial cells.

Abstract

Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are the predominant gelatinases in the developing lung. Studies have shown that the expression of MMP-2 and MMP-9 is upregulated in hypoxic fibroblasts, 15-hydroxyeicosatetraenoic acid (15-HETE) regulated fibroblasts migration via modulating MMP-2 or MMP-9, and that hypoxia/15-HETE is a predominant contributor to the development of pulmonary arterial hypertension (PAH) through increased angiogenesis. However, the roles of MMP-2 and MMP-9 in pulmonary arterial endothelial cells (PAECs) angiogenesis as well as the molecular mechanism of hypoxia-regulated MMP-2 and MMP-9 expression have not been identified. The aim of this study was to investigate the role of MMP-2 and MMP-9 in PAEC proliferation and vascular angiogenesis and to determine the effects of hypoxia-induced 15-HETE on the expression of MMP-2 and MMP-9. Western blot, immunofluorescence, and real-time PCR were used to measure the expression of MMP-2 and MMP-9 in hypoxic PAECs. Immunohistochemical staining, flow cytometry, and tube formation as well as cell proliferation, viability, scratch-wound, and Boyden chamber migration assays were used to identify the roles and relationships between MMP-2, MMP-9, and 15-HETE in hypoxic PAECs. We found that hypoxia increased MMP-2 and MMP-9 expression in pulmonary artery endothelium both in vivo and in vitro in a time-dependent pattern. Moreover, administration of the MMP-2 and MMP-9 inhibitor MMI-166 significantly reversed hypoxia-induced increases in right ventricular systemic pressure (RVSP), right ventricular function, and thickening of the tunica media. Furthermore, up-regulation of MMP-2 and MMP-9 expression was induced by 15-HETE, which regulates PAEC proliferation, migration, and cell cycle transition that eventually leads to angiogenesis. Our study demonstrated that hypoxia increases the expression of MMP-2 and MMP-9 through the 15-lipoxygenase/15-HETE pathway, and that MMP-2 and MMP-9 promote PAEC angiogenesis. These findings suggest that MMP-2 and MMP-9 may serve as new potential therapeutic targets for the treatment of PAH.

• Authors: Ying Liu, Hongyue Zhang, Lixin Yan, Wei Du, Min Zhang, He Chen, Lixin Zhang, Guangqun Li, Jijin Li, Yinchu Dong, Daling Zhu
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 121 Pg. 36-50 (08 2018) ISSN: 1095-8584 [Electronic] England
• PMID: 29913136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Hydroxyeicosatetraenoic Acids
• N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan
• Sulfonamides
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid
• Alox15 protein, mouse
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Arachidonate 12-Lipoxygenase (genetics)
• Arachidonate 15-Lipoxygenase (genetics)
• Blood Pressure (drug effects, genetics)
• Cell Hypoxia (genetics)
• Cell Movement (genetics)
• Cell Proliferation (drug effects)
• Endothelial Cells (drug effects, pathology)
• Gene Expression Regulation, Developmental (drug effects)
• Humans
• Hydroxyeicosatetraenoic Acids (genetics, metabolism)
• Hypertension, Pulmonary (drug therapy, genetics, metabolism, pathology)
• Lung (drug effects, pathology)
• Matrix Metalloproteinase 2 (genetics)
• Matrix Metalloproteinase 9 (genetics)
• Mice
• Neovascularization, Pathologic (drug therapy, genetics, pathology)
• Pulmonary Artery (metabolism, pathology)
• Sulfonamides (pharmacology)
• Tunica Media (metabolism, pathology)