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

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 Matthew Black, Sohrab Fratz, Jeffrey R. Fineman, James D. West, Kathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Katherine A. CottrillStephen Y. Chan

Research output: Contribution to journalArticle

120 Citations (Scopus)

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 miRNAdisease 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.

Original languageEnglish (US)
Pages (from-to)3514-3528
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

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MicroRNAs
Pulmonary Hypertension
Smooth Muscle Myocytes
Endothelial Cells
Peroxisome Proliferator-Activated Receptors
Gene Regulatory Networks
Fibroblast Growth Factor 2
Vascular Diseases
Lung Diseases
Up-Regulation
Cell Proliferation
Phenotype
Lung

ASJC Scopus subject areas

  • Medicine(all)

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Bertero, T., Lu, Y., Annis, S., Hale, A., Bhat, B., Saggar, R., ... Chan, S. Y. (2014). Systems-level regulation of MicroRNA networks by miR-130/301 promotes pulmonary hypertension. Journal of Clinical Investigation, 124(8), 3514-3528. https://doi.org/10.1172/JCI74773

Systems-level regulation of MicroRNA networks by miR-130/301 promotes pulmonary hypertension. / Bertero, Thomas; Lu, Yu; Annis, Sofia; Hale, Andrew; Bhat, Balkrishen; Saggar, Rajan; Saggar, Rajeev; Wallace, W. Dean; Ross, David J.; Vargas, Sara O.; Graham, Brian B.; Kumar, Rahul; Black, Stephen Matthew; Fratz, Sohrab; Fineman, Jeffrey R.; West, James D.; Haley, Kathleen J.; Waxman, Aaron B.; Chau, B. Nelson; Cottrill, Katherine A.; Chan, Stephen Y.

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3514-3528.

Research output: Contribution to journalArticle

Bertero, T, Lu, Y, Annis, S, Hale, A, Bhat, B, Saggar, R, Saggar, R, Wallace, WD, Ross, DJ, Vargas, SO, Graham, BB, Kumar, R, Black, SM, Fratz, S, Fineman, JR, West, JD, Haley, KJ, Waxman, AB, Chau, BN, Cottrill, KA & Chan, SY 2014, 'Systems-level regulation of MicroRNA networks by miR-130/301 promotes pulmonary hypertension', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3514-3528. https://doi.org/10.1172/JCI74773
Bertero, Thomas ; Lu, Yu ; Annis, Sofia ; Hale, Andrew ; Bhat, Balkrishen ; Saggar, Rajan ; Saggar, Rajeev ; Wallace, W. Dean ; Ross, David J. ; Vargas, Sara O. ; Graham, Brian B. ; Kumar, Rahul ; Black, Stephen Matthew ; Fratz, Sohrab ; Fineman, Jeffrey R. ; West, James D. ; Haley, Kathleen J. ; Waxman, Aaron B. ; Chau, B. Nelson ; Cottrill, Katherine A. ; Chan, Stephen Y. / Systems-level regulation of MicroRNA networks by miR-130/301 promotes pulmonary hypertension. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3514-3528.
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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 miRNAdisease 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.",
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AU - Lu, Yu

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AU - Hale, Andrew

AU - Bhat, Balkrishen

AU - Saggar, Rajan

AU - Saggar, Rajeev

AU - Wallace, W. Dean

AU - Ross, David J.

AU - Vargas, Sara O.

AU - Graham, Brian B.

AU - Kumar, Rahul

AU - Black, Stephen Matthew

AU - Fratz, Sohrab

AU - Fineman, Jeffrey R.

AU - West, James D.

AU - Haley, Kathleen J.

AU - Waxman, Aaron B.

AU - Chau, B. Nelson

AU - Cottrill, Katherine A.

AU - Chan, Stephen Y.

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