miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling.

Abstract

Chronic hypoxia causes pulmonary vascular remodeling leading to pulmonary hypertension (PH) and right ventricle (RV) hypertrophy. Aberrant expression of microRNA (miRNA) is closely associated with a number of pathophysiologic processes. However, the role of miRNAs in chronic hypoxia-induced pulmonary vascular remodeling and PH has not been well characterized. In this study, we found increased expression of miR-21 in distal small arteries in the lungs of hypoxia-exposed mice. Putative miR-21 targets, including bone morphogenetic protein receptor (BMPR2), WWP1, SATB1, and YOD1, were downregulated in the lungs of hypoxia-exposed mice and in human pulmonary artery smooth muscle cells (PASMCs) overexpressing miR-21. We found that sequestration of miR-21, either before or after hypoxia exposure, diminished chronic hypoxia-induced PH and attenuated hypoxia-induced pulmonary vascular remodeling, likely through relieving the suppressed expression of miR-21 targets in the lungs of hypoxia-exposed mice. Overexpression of miR-21 enhanced, whereas downregulation of miR-21 diminished, the proliferation of human PASMCs in vitro and the expression of cell proliferation associated proteins, such as proliferating cell nuclear antigen, cyclin D1, and Bcl-xL. Our data suggest that miR-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling and also suggest that miR-21 is a potential target for novel therapeutics to treat chronic hypoxia associated pulmonary diseases.

• Authors: Shanzhong Yang, Sami Banerjee, Andressa de Freitas, Huachun Cui, Na Xie, Edward Abraham, Gang Liu
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 302 Issue 6 Pg. L521-9 (Mar 15 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22227207 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2L1 protein, human
• CCND1 protein, human
• Cell Cycle Proteins
• MIRN21 microRNA, mouse
• Matrix Attachment Region Binding Proteins
• MicroRNAs
• Satb1 protein, mouse
• bcl-X Protein
• Cyclin D1
• WWP1 protein, mouse
• Ubiquitin-Protein Ligases
• Bmpr2 protein, mouse
• Bone Morphogenetic Protein Receptors, Type II

Topics

• Airway Remodeling (genetics, physiology)
• Animals
• Apoptosis (genetics)
• Bone Morphogenetic Protein Receptors, Type II (genetics, metabolism)
• Cell Cycle Proteins (genetics)
• Cell Line
• Cell Proliferation
• Cyclin D1 (genetics, metabolism)
• Down-Regulation (genetics)
• Humans
• Hypertension, Pulmonary (etiology, genetics, metabolism, physiopathology)
• Hypertrophy, Right Ventricular (genetics, metabolism, physiopathology)
• Hypoxia (complications, genetics, metabolism, physiopathology)
• Lung (metabolism, physiopathology)
• Matrix Attachment Region Binding Proteins (genetics, metabolism)
• Mice
• MicroRNAs (genetics)
• Muscle, Smooth, Vascular (metabolism, physiopathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Pulmonary Artery (metabolism, physiopathology)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Up-Regulation (genetics)
• bcl-X Protein (genetics, metabolism)