Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension

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dc.contributor.authorMorecroft, I.
dc.contributor.authorWhite, K.
dc.contributor.authorCaruso, P.
dc.contributor.authorNilsen, M.
dc.contributor.authorLoughlin, L.
dc.contributor.authorAlba, R.
dc.contributor.authorReynolds, P.
dc.contributor.authorDanilov, S.
dc.contributor.authorBaker, A.
dc.contributor.authorMacLean, M.
dc.date.issued2012
dc.description.abstractSerotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of a gene therapy approach to PAH using selective inhibition of PAEC-Tph1 in vivo in a hypoxic model of PAH. We exposed cultured bovine pulmonary arterial smooth muscle cells (bPASMCs) to conditioned media from human PAECs (hPAECs) before and after hypoxic exposure. Serotonin levels were increased in hypoxic PAEC media. Conditioned media evoked bPASMC proliferation, which was greater with hypoxic PAEC media, via a serotonin-dependent mechanism. In vivo, adenoviral vectors targeted to PAECs (utilizing bispecific antibody to angiotensin-converting enzyme (ACE) as the selective targeting system) were used to deliver small hairpin Tph1 RNA sequences in rats. Hypoxic rats developed PAH and increased lung Tph1. PAEC-Tph1 expression and development of PAH were attenuated by our PAEC-Tph1 gene knockdown strategy. These results demonstrate that hypoxia induces Tph1 activity and selective knockdown of PAEC-Tph1 attenuates hypoxia-induced PAH in rats. Further investigation of pulmonary endothelial-specific Tph1 inhibition via gene interventions is warranted.
dc.description.statementofresponsibilityIan Morecroft, Katie White, Paola Caruso, Margaret Nilsen, Lynn Loughlin, Raul Alba, Paul N. Reynolds, Sergei M. Danilov, Andrew H. Baker and Margaret R. MacLean
dc.identifier.citationMolecular Therapy, 2012; 20(8):1516-1528
dc.identifier.doi10.1038/mt.2012.70
dc.identifier.issn1525-0016
dc.identifier.issn1525-0024
dc.identifier.orcidReynolds, P. [0000-0002-2273-1774]
dc.identifier.urihttp://hdl.handle.net/2440/73709
dc.language.isoen
dc.publisherAcademic Press Inc Elsevier Science
dc.rights© The American Society of Gene & Cell Therapy
dc.source.urihttps://doi.org/10.1038/mt.2012.70
dc.subjectEndothelial Cells
dc.subjectAnimals
dc.subjectCattle
dc.subjectHumans
dc.subjectRats
dc.subjectAdenoviridae
dc.subjectHypertension, Pulmonary
dc.subjectTryptophan Hydroxylase
dc.subjectCell Proliferation
dc.subjectGenetic Vectors
dc.subjectGenetic Therapy
dc.subjectFamilial Primary Pulmonary Hypertension
dc.subjectHypoxia
dc.titleGene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension
dc.typeJournal article
pubs.publication-statusPublished

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