Regulación Génica en Remodelado Vascular e Inflamación
Our group is interested in the molecular mechanisms regulating vascular and cardiac remodeling, including those mediated by genes regulated by angiotensin-II (AngII) and calcineurin (CN). Part of our previous work related to molecular interactions of CN with substrates (Rodriguez et al Mol Cell 2009; Martínez et al PNAS 2009) and to the modulation of inflammatory responses by specific CN targeting (Escolano et al EMBO J 2014). We also found that genes regulated by the CN-NFAT pathway play a major role in cardiac hypertrophy (CH) and angiogenesis (Hernández et al J Exp Med 2001; Urso et al Blood 2011; Alfranca et al Blood 2008, Martínez et al FEBS J 2020). Another main focus is the role of AngII and CN pathways in vascular and cardiac remodeling, and we have set up mouse models of atherosclerosis, aneurysm, intramural hematoma and restenosis. Our work shows that CN and its downstream effectors Rcan1 and PMCA mediate vascular damage in these diseases (Mendez EMBO Mol Med 2013; Baggott et al ATVB 2014; Villahoz et al Nat Comm 2018). We are currently elucidating the mechanisms that induce vascular damage and CH, and we have generated conditional mice deficient for CN and several of its downstream effectors in endothelium, vascular smooth muscle, and cardiomyocytes using inducible controllers specific for each cell type. We are using these mice to define the role of vascular and endothelial CN in thoracic and abdominal aortic aneurysm and blood pressure and the role of cardiomyocyte CN in CH.
Our recent efforts have focused on dissecting the mechanisms involved in aortic diseases such as familial forms of thoracic aortic aneurysm and dissection (TAAD), including Marfan syndrome (MFS). This work has led to the discovery of novel genes that mediate aortic diseases, including Adamts1, Rcan-1, Nos2 C/EBPβ, and Plk1 (Oller et al, Mol Cell Biol 2015; Oller et al, Nat Med 2017; de Carcer et al Nat Med 2017; Villahoz et al Nat Comm 2018). We have identified new mechanisms and targets in aortic diseases, showing that Adamts1 deficiency leads to aortic disease in mice due to increased NOS2-dependent NO production. Decreased Adamts1 and increased NOS2 expression occur in MFS mice and patients. Our results point to the potential of NOS2 inhibitors in the treatment of TAAD, since NOS2 inhibition prevents and reverses aortic pathology in MFS mice (Nat Med 2017a). The group has also pioneered studies showing that the NO–sGC–PRKG pathway is overactivated in MFS mice and patients and mediates aortopathy in MFS mice (de la Fuente et al, Nat Comm 2021). These studies represent key contributions to the understanding of the pathophysiology of TAAD, and we plan to continue to identify new biomarkers and therapeutic targets in syndromic and non-syndromic aortic diseases.