Rivera-Torres José, Guzmán-Martínez Gabriela, Villa-Bellosta Ricardo, Orbe Josune, González-Gómez Cristina, Serrano Manuel, Díez Javier, Andrés Vicente, Maraver Antonio
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.
J Hypertens. 2015 Apr;33(4):843-50; discussion 850. doi: 10.1097/HJH.0000000000000463.
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).
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.
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.
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.
Notch信号通路已被证实与肺动脉高压有关，但其在系统性高血压，尤其是左心室肥厚（LVH）中的作用仍知之甚少。本研究的主要目的是分析抑制Notch信号通路对成年小鼠因诱导性基因缺失γ-分泌酶而导致的血管紧张素II（Ang-II）诱导的动脉高血压和LVH的建立与维持的影响，并在临床前测试γ-分泌酶抑制剂（GSIs）的治疗效果。
我们分析了从一种新型小鼠模型获得的血管平滑肌细胞原代培养物中对Ang-II的反应，该模型具有诱导性基因缺失γ-分泌酶复合物，以及GSI处理对小鼠心脏细胞系的影响。我们还研究了在我们缺乏γ-分泌酶复合物的新型小鼠品系以及GSI处理的野生型小鼠中Ang-II诱导的高血压和LVH。此外，我们分析了有和没有LVH的高血压患者的血管组织。
血管平滑肌细胞在体外和体内对Ang-II的反应中激活Notch信号通路。成年小鼠中γ-分泌酶的基因缺失可预防Ang-II诱导的高血压和LVH，且不会引起重大不良反应。GSI处理可在体外减少Ang-II诱导的心脏细胞系肥大，并在接受Ang-II攻击的野生型小鼠中减少LVH。我们还报告，与没有LVH的高血压患者相比，有LVH的高血压患者血管组织中Notch靶标HES5的表达升高。
在患有高血压和LVH的小鼠血管系统中，Notch信号通路被激活，通过诱导性基因γ-分泌酶缺失对其进行抑制可预防这两种情况。对有LVH的高血压患者的初步观察支持了这些发现的转化潜力。此外，GSI处理可保护野生型小鼠免受Ang-II诱导的LVH，而不影响血压。我们的结果揭示了GSIs在治疗有LVH的高血压患者中的潜在用途。
