2026-04-30T10:28:19Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/79222024-09-27T08:29:00Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Rivera-Torres, Jose
author
Guzman-Martinez, Gabriela
author
Villa-Bellosta, Ricardo
author
Orbe, Josune
author
Gonzalez-Gomez, Cristina
author
Serrano, Manuel
author
Díez, Javier
author
Andres, Vicente
author
Maraver, Antonio
funder
Ministerio de Economía y Competitividad (España)
funder
Instituto de Salud Carlos III
funder
Fundación ProCNIC
2019-07-17T08:14:26Z
2019-07-17T08:14:26Z
2015-04
Fisiopatología Cardiovascular Molecular y Genética
10.1097/HJH.0000000000000463
1473-5598
0263-6352
Journal of hypertension
25915889
http://hdl.handle.net/20.500.12105/7922
OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of γ-secretase, and to test preclinically the therapeutic efficacy of γ-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the γ-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the γ-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of γ-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic γ-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.
eng
Targeting γ-secretases protect against angiotensin II-induced cardiac hypertrophy
journal article
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TargetingGammaSecretasesProtect_2015.pdf
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TargetingGammaSecretasesProtect_2015_SupplMat.pdf
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TargetingGammaSecretasesProtect_2015.pdf.txt
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