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

Morecroft, I., White, K., Caruso, P., Nilsen, M., Loughlin, L., Alba, R., Reynolds, P.N., Danilov, S.M., Baker, A.H. and MacLean, M.R. (2012) Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension. Molecular Therapy, 20(8), pp. 1516-1528. (doi: 10.1038/mt.2012.70)

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Abstract

Serotonin 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Baker, Professor Andrew and White, Miss Katie and Alba, Dr Raul and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Morecroft, Dr Ian and Caruso, Ms Paola
Authors: Morecroft, I., White, K., Caruso, P., Nilsen, M., Loughlin, L., Alba, R., Reynolds, P.N., Danilov, S.M., Baker, A.H., and MacLean, M.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Molecular Therapy
Journal Abbr.:Mol. Ther.
ISSN:1525-0016
ISSN (Online):1525-0024
Published Online:24 April 2012

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