Identification of the metalloproteinase adamts1 and nitric oxide as new therapeutic targets in aortic diseases

Resumen

The main cause of cardiovascular diseases is the pathological vascular remodeling. This process is the cause of the cys c medial degenera on of the aor c wall that produces a weakening and, therefore, an increased risk of aneurysms. An aneurysm is a localized dila on of an artery and may be causa ve of an arterial dissec on. Some gene c disorders such as Marfan Syndrome are prone to aor c aneurysms. Currently, there is no pharmacological treatment to slow or decrease the size of the aneurysm and to prevent its dissec on. Previous studies indicate that extracellular matrix metalloproteinases play a key role during the vascular remodeling process. Moreover, previous reports show that extracellular metaloprotease Adamts1 could play an important role in homeostasis and vascular pathology. However, the speci c role of Adamts1 in vascular homeostasis and in the development of aor c aneurysm is unknown. The main objec ve of this work was to determine, on one hand, the mechanisms and molecular mediators by which Adamts1 is expressed in the vasculature and, on the other hand, the func ons of this metalloprotease in vascular homeostasis and in the development of aor c aneurysm. First, we elucidate that di erent remodeling agents such as VEGF, Ang-II, IL1-β and TNF-α induce the expression of Adamts1 di eren ally in s mulus-dependent vascular cells. This regula on is due to a di eren al ac va on of transcrip on factors: VEGF through Calcineurin-NFAT pathway and the phosphoryla on of C/EBPβ by Ang-II, IL1β and TNF-α induce a increase in the expression of Adamts1 in vascular cells in vitro and in vivo. Finally, we have described the func onal role of Adamts1 in the vascular wall. In this case, we have observed that Adamts1-de cient mice have characteris cs similar to Marfan Syndrome such as: longer bone length, hyperkinesis, and pulmonary emphysema and a higher incidence of aor c aneurysms. On the other hand, we have analyzed in detail the molecular mechanisms in which this metalloproteinase is involved in aneurysms. In this case, we have found that Adamts1 de ciency induces an increase of expression of inducible nitric oxide synthase (NOS2) and in Nitric Oxide (NO). Subsequently, we have found that both, mice and pa ents with Marfan Syndrome have decreased levels of Adamts1 that correlate with increased levels of NOS2 and NO. The ac vity of NOS2 would be responsible for the induced aortopathy in both models, since speci c inhibitors of NOS2 reduce the aor c dila on and the degenera on of the Tunica Media in Marfan and Adamts1-de cient mice. Therefore, in this work we have described new molecular mechanisms and therapeu c targets that are present in aor c diseases, that nowadays have no treatment. All these results provide new mediators targets such as ADAMTS1 and NOS2 in aor c diseases, speci cally in Marfan Syndrome.