A Sex-Specific MicroRNA-96/5-Hydroxytryptamine 1B Axis Influences Development of Pulmonary Hypertension

Emma Wallace, Nicholas W Morrell, Xudong D Yang, Lu Long, Hannah Stevens, Margaret Nilsen, Lynn Loughlin, Kirsty M Mair, Andrew H Baker, Margaret R MacLean

Research output: Contribution to journalArticlepeer-review

Abstract

RATIONALE: Females are predisposed to pulmonary arterial hypertension (PAH); evidence suggests that serotonin, mutations in the bone morphogenetic protein receptor (BMPR) II gene, and estrogens influence development of PAH. The 5-hydroxytryptamine 1B receptor (5-HT1BR) mediates human pulmonary artery smooth muscle cell (hPASMC) proliferation.

OBJECTIVES: We aimed to determine whether selected microRNAs (miRNAs) expressed in PASMCs are influenced by sex, BMPR-II mutations, and estrogens, and contribute to PASMC proliferation in PAH.

METHODS: Expression levels of miRNAs targeting genes related to PAH, estrogen, and serotonin were determined by quantitative RT-PCR in hPASMCs and mouse PASMCs harboring a heterozygous mutation in BMPR-II (BMPR-IIR899X+/− PASMCs). miRNA-96 targets 5-HT1BR and was selected for further investigation. miRNA target validation was confirmed by luciferase reporter assay. Precursor miRNA-96 was transfected into hPASMCs to examine effects on proliferation and 5-HT1BR expression. The effect of a miRNA-96 mimic on the development of hypoxic pulmonary hypertension in mice was also assessed.

MEASUREMENTS AND MAIN RESULTS: miRNA-96 expression was reduced in BMPR-IIR899X+/− PASMCs from female mice and hPASMCs from female patients with PAH; this was associated with increased 5-HT1BR expression and serotonin-mediated proliferation. 5-HT1BR was validated as a target for miRNA-96. Transfection of precursor miRNA-96 into hPASMCs reduced 5-HT1BR expression and inhibited serotonin-induced proliferation. Restoration of miRNA-96 expression in pulmonary arteries in vivo via administration of an miRNA-96 mimic reduced the development of hypoxia-induced pulmonary hypertension in the mouse.

CONCLUSIONS: Increased 5-HT1BR expression may be a consequence of decreased miRNA-96 expression in female patient PASMCs, and this may contribute to the development of PAH.
Original languageEnglish
Pages (from-to)1432-1442
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number12
Early online date14 Apr 2015
DOIs
Publication statusPublished - 15 Jun 2015

Keywords

  • Animals
  • Bone Morphogenetic Protein Receptors, Type II
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hypertension, Pulmonary
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs
  • Muscle, Smooth, Vascular
  • Pulmonary Artery
  • Real-Time Polymerase Chain Reaction
  • Receptor, Serotonin, 5-HT1B
  • Sex Characteristics
  • Signal Transduction

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