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

White, K., Loughlin, L., Maqbool, Z., Nilsen, M., McClure, J. , Dempsie, Y., Baker, A. H. and MacLean, M. R. (2011) Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiological Genomics, 43(8), pp. 417-437. (doi:10.1152/physiolgenomics.00249.2010)

White, K., Loughlin, L., Maqbool, Z., Nilsen, M., McClure, J. , Dempsie, Y., Baker, A. H. and MacLean, M. R. (2011) Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiological Genomics, 43(8), pp. 417-437. (doi:10.1152/physiolgenomics.00249.2010)

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Publisher's URL: http://dx.doi.org/10.1152/physiolgenomics.00249.2010

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Baker, Professor Andrew and Maqbool, Dr Zakia and White, Dr Kevin and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and McClure, Dr John
Authors: White, K., Loughlin, L., Maqbool, Z., Nilsen, M., McClure, J., Dempsie, Y., Baker, A. H., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Physiological Genomics
Publisher:American Physiological Society
ISSN:1094-8341
ISSN (Online):1531-2267
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
490991Effect of oestrogen on the serotonin system: role in the development of pulmonary hypertensionMargaret MacleanMedical Research Council (MRC)G0801171RI CARDIOVASCULAR & MEDICAL SCIENCES
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES