Regulator of calcineurin 1 mediates pathological vascular wall remodeling
Por:
Esteban V., Méndez-Barbero N., Jiménez-Borreguero L.J., Roqué M., Novensá L., García-Redondo A.B., Salaices M., Vila L., Arbonés M.L., Campanero M.R., Redondo J.M.
Publicada:
1 ene 2011
Resumen:
Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1 -/- mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression. © 2011 Esteban et al.
Filiaciones:
Esteban V.:
Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain
Méndez-Barbero N.:
Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain
Jiménez-Borreguero L.J.:
Department of Atherotrombosis and Imaging, CNIC and Hospital de la Princesa, E-28029 Madrid, Spain
Roqué M.:
Department of Cardiology, Institut del Tòrax, Institut d'Investigacions Biomèdiques Agustí Pi Sunyer, Hospital Clínic, 08036 Barcelona, Spain
Novensá L.:
Department of Cardiology, Institut del Tòrax, Institut d'Investigacions Biomèdiques Agustí Pi Sunyer, Hospital Clínic, 08036 Barcelona, Spain
García-Redondo A.B.:
Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
Salaices M.:
Department of Pharmacology, Facultad de Medicina, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
Vila L.:
Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), E-08025 Barcelona, Spain
Arbonés M.L.:
Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), E-08028, Barcelona, Spain
Campanero M.R.:
Department of Cancer Biology, Instituto de Investigaciones Biomedicas Alberto Sols, CSIC-UAM, E-28029 Madrid, Spain
Redondo J.M.:
Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain
Green Published, Hybrid Gold, All Open Access, Green
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