The NO signaling pathway in aortic disease

Speaker: Juan Miguel Redondo

Centro Nacional de Investigaciones Cardiovasculares (CNIC) [Madrid, Spain]

Host: Pedro A. Lazo-Zbikowski

Fecha: 22/11/2018

Hora: 12:30

Salón de Actos del Centro de Investigación del Cáncer

During the last few years, we have identified a number of genes that are involved in thoracic aortic aneurysm and dissection (TAAD) and in other diseases that occur with pathological wall remodeling. These genes include Rcan1, Calcineurin, Adamts1, Nos2, C/EBPβ and Plk1. We have found that Adamts1 is a major regulator of vascular homeostasis whose genetic haploinsufficiency in mice causes a TAAD similar to Marfan Syndrome (MFS). Unexpectedly, aortic nitric oxide and Nos2 levels are increased in Adamts1-deficient mice before TGFß activation, and Nos2 inactivation protects both Adamts1^+/- mice and a mouse model of MFS from developing aortopathy. More importantly, pharmacological inhibition of NOS2 results in a rapid and sustained reversion of aortic dilation and medial degeneration in Adamts1-deficient mice and in MFS mice. MFS patients also show elevated NOS2 and downregulated ADAMTS1 in aorta, uncovering a possible causative role for this axis in human disease. We are currently investigating the relative roles and expression of different members and substrates of the ADAMTS family in aortic dilation and medial degeneration in MFS mouse models and MFS patients. We believe that these findings open new exciting avenues of research into TAADs pathogenesis and urge the evaluation of NOS2 inhibitors as a novel therapy.