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Published on: September 28, 2015
Targeting γ-secretases protect against angiotensin II-induced cardiac hypertrophy
José Rivera-Torres1, Gabriela Guzmán-Martínez, Ricardo Villa-Bellosta
1aDepartment of Atherothrombosis Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC) bCardiac Imaging Unit, Cardiology Department, Hospital Universitario La Paz, IdiPaz, Madrid cProgram of Cardiovascular Diseases, Centre of Applied Medical Research, University of Navarra, Pamplona dTumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid eDepartment of Cardiology and Cardiac Surgery, University Clinic of Navarra, University of Navarra, Pamplona, Spain fInstitute de Recherche en Cancérologie de Montpellier (IRCM), Montpellier, France *Both Antonio Maraver and Vicente Andrés equally contributed to this work.
Insights
Inhibiting the Notch pathway prevents and treats hypertension and left ventricular hypertrophy (LVH) in mice by blocking gamma-secretase. This suggests gamma-secretase inhibitors (GSIs) may treat hypertensive patients with LVH.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Hypertension Research
Background:
- The Notch pathway's role in systemic hypertension and left ventricular hypertrophy (LVH) is not well understood.
- Pulmonary hypertension is linked to the Notch pathway, but its systemic effects are unclear.
Purpose of the Study:
- To investigate the Notch pathway's role in angiotensin II (Ang-II)-induced hypertension and LVH.
- To analyze the effects of inhibiting the Notch pathway on established and developing hypertension and LVH.
- To evaluate the preclinical therapeutic potential of gamma-secretase inhibitors (GSIs).
Main Methods:
- Utilized a novel mouse model with inducible genetic deletion of the gamma-secretase complex.
- Analyzed Ang-II responses in vascular smooth muscle cells and a cardiac cell line.
- Investigated hypertension and LVH in gamma-secretase deficient mice and GSI-treated wild-type mice.
- Examined vascular tissue from hypertensive patients with and without LVH.
Main Results:
- Vascular smooth muscle cells activate the Notch pathway in response to Ang-II.
- Genetic deletion of gamma-secretase prevented Ang-II-induced hypertension and LVH in mice.
- GSI treatment reduced cardiac cell hypertrophy and LVH in wild-type mice.
- Elevated Notch target HES5 expression was observed in hypertensive patients with LVH.
Conclusions:
- The Notch pathway is activated in the vasculature during hypertension and LVH.
- Inhibiting the Notch pathway via gamma-secretase deletion protects against hypertension and LVH.
- GSIs show therapeutic potential for treating hypertensive patients with LVH, without affecting blood pressure.
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.
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