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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 Article has an altmetric score of 37

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

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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 7

Forced expression of miR-130a induces PH in a PPARγ-dependent manner in vivo.

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Forced expression of miR-130a induces PH in a PPARγ-dependent manner in ...
(A) Serial intrapharyngeal delivery of miR-130a mimic oligonucleotide (miR-130a) increased miR-130a in whole lung in mice as compared with control (miR-NC), either with or without daily oral dosing of rosiglitazone (Rosi). See Supplemental Figure 18 for protocol design. (B) MiR-130a increased right ventricular systolic pressure (RVSP) compared with control (miR-NC), an effect reversed by rosiglitazone. See Supplemental Figure 21A for quantification of right ventricle/(left ventricle + septum) (RV/LV+S) mass ratio. (C) By RT-qPCR of whole lung, miR-130a decreased miR-204, miR-322 (the mouse homolog of human miR-424), and miR-503 expression, but this effect was reversed by rosiglitazone. (D) IHC staining of pulmonary vessels less than 100 μm in diameter was performed to quantify PPARγ, PCNA, phosphorylated STAT3 (P-STAT3), and α-SMA. Ten vessels were quantified for each mouse (bar graphs). Consistent with data from cultured cells (Figures 5 And 6), miR-130a decreased PPARγ expression (top row); increased PCNA-positive (second row) and P-STAT3–positive (third row) cells (quantified over 10 vessels); and increased medial thickness (bottom row) consistent with exaggerated vascular remodeling. See Supplemental Figure 21B for arteriolar density, Supplemental Figure 21C for arteriolar muscularization, and Supplemental Figure 21, D and E, for gene expression by immunoblotting. In A and C, for each miRNA, mean expression in control groups (miR-NC) was assigned a fold change of 1, to which relevant samples were compared. In experiments involving animal tissue (A–C), data are expressed as mean ± SEM, while IHC quantification (D) is expressed as mean ± SD (*P < 0.05; **P < 0.01). Scale bar: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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