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

J Clin Invest. 2014 Aug;124(8):3514-28. doi: 10.1172/JCI74773. Epub 2014 Jun 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apelin
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation
  • Computer Simulation
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Fibroblast Growth Factor 2 / metabolism
  • Gene Regulatory Networks
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / pathology
  • Hypoxia / complications
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Biological
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Octamer Transcription Factor-3 / metabolism
  • PPAR gamma / metabolism
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Systems Theory
  • Up-Regulation

Substances

  • APLN protein, human
  • Apelin
  • Basic Helix-Loop-Helix Transcription Factors
  • Intercellular Signaling Peptides and Proteins
  • MIRN130 microRNA, human
  • MIRN130 microRNA, mouse
  • MIRN301 microRNA, human
  • MIRN301 microRNA, mouse
  • MicroRNAs
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • PPAR gamma
  • STAT3 Transcription Factor
  • Fibroblast Growth Factor 2
  • endothelial PAS domain-containing protein 1