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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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 4

Expression of the miR-130/301 family is upregulated in diverse forms of human PAH.

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Expression of the miR-130/301 family is upregulated in diverse forms of ...
In situ hybridization of human lung (A) and quantification of pulmonary vessels less than 200 μm in diameter (10 vessels per patient) (B) revealed increased miR-130a in diseased pulmonary vessels of 6 patients suffering from PAH stemming from a variety of causes as well as in vessels from 13 patients with scleroderma-induced PAH as compared with 4 healthy controls (no PH). By digital zoom (dotted red frame), staining of the intimal and medial layers of the vessel wall was evident (red arrowheads denote intimal layer). See also Supplemental Table 7 for patient demographics. (C) Increasingly higher plasma levels of miR-130/301 family members were observed in patients with increasing hemodynamic severity of PH. Here, 5 non-PH controls (mPAP < 25 mmHg) were compared with PH patients stratified by hemodynamic severity — 7 patients with mPAP 25–45 mmHg and 7 patients with mPAP greater than 45 mmHg. See also Supplemental Table 8. Statistically significant differences are indicated (**P < 0.01). In the physiologic experiment (C), data are expressed as mean ± SEM, while in the in situ quantitations (B), data are expressed as mean ± SD. Tissue scale bar: 50 μm.