Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH

Kevin White, Lynn Loughlin, Zakia Maqbool, Margaret Nilsen, John McClure, Yvonne Dempsie, Andrew H Baker, Margaret R MacLean

Research output: Contribution to journalArticlepeer-review

Abstract

Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPβ, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPβ, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPβ, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPβ, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17β-estradiol increased CEBPβ, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPβ, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH.

Original languageEnglish
Pages (from-to)417-37
Number of pages21
JournalPhysiological Genomics
Volume43
Issue number8
DOIs
Publication statusPublished - 27 Apr 2011

Keywords

  • Animals
  • Animals, Genetically Modified
  • Anoxia
  • Aryl Hydrocarbon Hydroxylases
  • CCAAT-Enhancer-Binding Protein-beta
  • Cell Culture Techniques
  • Cytochrome P-450 CYP1B1
  • Drug-Induced Liver Injury, Chronic
  • Estrogens
  • Familial Primary Pulmonary Hypertension
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Hypertension, Pulmonary
  • Male
  • Mice
  • Microarray Analysis
  • Myocytes, Smooth Muscle
  • Proto-Oncogene Proteins c-fes
  • Pulmonary Artery
  • Serotonin Plasma Membrane Transport Proteins
  • Sex

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