title: Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH.
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.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.forename: Zakia
authors.initials: Z
authors.lastname: Maqbool
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.forename: John
authors.initials: J
authors.lastname: McClure
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D018929:Cell Culture Techniques; D056487:Chemical and Drug Induced Liver Injury, Chronic; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000235:genetics; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D046228:Microarray Analysis / Q000379:methods*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051578:Proto-Oncogene Proteins c-fes / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D012723:Sex
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D004967:Estrogens; D050486:Serotonin Plasma Membrane Transport Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D051578:Proto-Oncogene Proteins c-fes