Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension
Thomas Bertero, … , Katherine A. Cottrill, Stephen Y. Chan
Thomas Bertero, … , Katherine A. Cottrill, Stephen Y. Chan
Published June 24, 2014
Citation Information: J Clin Invest. 2014;124(8):3514-3528. https://doi.org/10.1172/JCI74773.
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Research Article Pulmonology

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Abstract

Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.

Authors

Thomas Bertero, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Sara O. Vargas, Brian B. Graham, Rahul Kumar, Stephen M. Black, Sohrab Fratz, Jeffrey R. Fineman, James D. West, Kathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Katherine A. Cottrill, Stephen Y. Chan

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Figure 1

In silico network-based analysis identifies the miR-130/301 family as a master regulator of subordinate miRNA pathways and PH.

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In silico network-based analysis identifies the miR-130/301 family as a ...
(A) The expanded PH network is color-coded according to functional pathway. Encircled areas represent architectural clusters based on a spectral partition-based clustering algorithm. The miR-130/301 family was ranked the highest by a miRNA spanning score, reflecting the most robust systems-level control over the expanded PH network as a whole. Direct targets of the miR-130/301 family (28 enlarged nodes) span all 8 gene clusters and 13 functional pathways. (B) The miR-130/301 family members share the same seed sequence (in red). (C) Direct targets of the miR-130/301 family, color-coded by functional pathway. (D) Predictions of downstream pathways connected to the miR-130/301 family and carrying the broadest influence on the expanded PH network, according to 4 scoring algorithms: (a) MiRNA spanning score: MiRNAs were ranked based on their network influence (see also Supplemental Table 2). (b) Target spanning score: Targets of miR-130/301 were ranked based on their network influence and the robustness of their relationship to the miR-130/301 family (see also Supplemental Table 3). (c) Gene spanning score: All network nodes were ranked based on their network influence (see also Supplemental Table 4). (d) Shared miRNA influence score: MiRNAs were ranked based on the overlap of their PH-relevant target pool with the miR-130/301 family (see also Supplemental Table 5).