Targeting γ-secretases protect against angiotensin II-induced cardiac hypertrophy.
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).


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.


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.


CONCLUSIONS
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.
aDepartment 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.
José
J
Rivera-Torres
Gabriela
G
Guzmán-Martínez
Ricardo
R
Villa-Bellosta
Josune
J
Orbe
Cristina
C
González-Gómez
Manuel
M
Serrano
Javier
J
Díez
Vicente
V
Andrés
Antonio
A
Maraver
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000517:prevention & control*; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D003984:Dibenzazepines; D000804:Angiotensin II; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine