Journal
CIRCULATION
Volume 125, Issue 12, Pages 1520-U216Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.111.060269
Keywords
microRNA; molecular biology; network biology; pulmonary heart disease; vasculature
Funding
- Sarnoff Cardiovascular Research Foundation
- American Heart Association [0825906D]
- National Institutes of Health [R37HL061795, U54HL070819, PO1HL48743, P50HL107192, U01HL108630]
- Lerner Fund
- Harris Fund
- Watkins Fund
- Gilead Research Scholars Fund
- Pulmonary Hypertension Association
- National Institutes of Health-Center of Excellence in Genomic Sciences
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Background-Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli. Methods and Results-Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH. Conclusions-A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH. (Circulation. 2012;125:1520-1532.)
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