Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction.

microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE-/- mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE-/- mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.V.G. de Yébenes was supported by Ramón y Cajal grant RYC-2009-04503 and AECC foundation grant INVES18013GARC and by the Universidad Complutense de Madrid. S.M. Mur and A.R. Ramiro are supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC) funding. A.R. Ramiro was supported by the Spanish Ministerio de Ciencia e Innovación (PID2019-107551RB-I00), the Spanish Ministerio de Economía, Industria y Competitividad (SAF2013-42767-R and SAF2016-75511-R), and the European Research Council StG BCLYM. M. Salaices was supported by the Ministerio de Ciencia e Innovación (SAF2016-80305P) and with J. Miguel Redondo by Instituto de Salud Carlos III (CIBER de Enfermedades Cardiovasculares, CB16/11/00286 and CB16/11/00264) and Comunidad de Madrid (B2017/BMD-3676). V.G. de Yébenes was supported by Ministerio de Ciencia e Innovación (PID2019-107551RB-I00). Further support was provided by the European Social Fund and the European Regional Development Fund “A Way to Build Europe.” The CNIC is supported by Ministerio de Ciencia, Innovacion y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Deciphering antibody-mediated atheroprotection to MDA-LDL

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 05-11-2021Esta tesis tiene embargado el acceso al texto completo hasta el 05-05-2023Atherosclerosis is a chronic inflammatory disease of the arteries that underlies the majority of cardiovascular events. Both innate and adaptive arms of immunity are involved in atherosclerosis initiation and progression. Neo-antigens resulting from endogenous modification of self-components are believed to be the main trigger for the adaptive immune response in atherosclerosis. The most paradigmatic of such neo-antigens are oxidized forms of LDL, and particularly, MDA-LDL. Indeed, immunization of pro-atherogenic mice and rabbits with MDA-LDL is atheroprotective. However, the immune response to MDA-LDL and the mechanisms responsible for this atheroprotection are not well understood. In this thesis, we have assessed the role of germinal center-derived antibodies in atherosclerosis and in MDA-LDL-driven atheroprotection. We have found that immunization of mice with MDA-LDL gives rise to memory B cells, IgG1 switched plasma cells and anti-MDA-LDL antibodies. Additionally, we have found that a fraction of antibodies generated upon MDA-LDL immunization recognize epitopes unique to MDA-LDL neo-antigen. High-throughput single cell immunoglobulin sequencing has revealed that MDA-LDL immunoglobulin repertoire is characterized by highly mutated antibodies. Thus, our data suggest that MDA-LDL behaves as a T-dependent antigen. To analyze the role of germinal center-derived antibodies in atherosclerosis, we have generated a mouse model lacking germinal center-derived plasma cells by conditional deletion of Blimp1. We have found that Blimp1-deficient mice show altered germinal center dynamics. Furthermore, Blimp1-deficient pro-atherogenic chimeras show accelerated atherosclerosis, suggesting an atheroprotective role of germinal center-derived antibodies in atherosclerosis. Finally, we have found that MDA-LDL immunization does not promote atheroprotection in mice lacking Blimp1, therefore indicating that germinal center-derived antibodies are required for MDA-LDL-driven atheroprotection. These findings support the idea that MDA-LDL-based vaccines could potentially be used for the prevention or treatment of atherosclerosi

Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction

microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE-/- mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE-/- mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.V.G. de Yébenes was supported by Ramón y Cajal grant RYC-2009-04503 and AECC foundation grant INVES18013GARC and by the Universidad Complutense de Madrid. S.M. Mur and A.R. Ramiro are supported by Centro Nacional de Investigaciones Cardiovasculares (CNIC) funding. A.R. Ramiro was supported by the Spanish Ministerio de Ciencia e Innovación (PID2019-107551RB-I00), the Spanish Ministerio de Economía, Industria y Competitividad (SAF2013-42767-R and SAF2016-75511-R), and the European Research Council StG BCLYM. M. Salaices was supported by the Ministerio de Ciencia e Innovación (SAF2016-80305P) and with J. Miguel Redondo by Instituto de Salud Carlos III (CIBER de Enfermedades Cardiovasculares, CB16/11/00286 and CB16/11/00264) and Comunidad de Madrid (B2017/BMD-3676). V.G. de Yébenes was supported by Ministerio de Ciencia e Innovación (PID2019-107551RB-I00). Further support was provided by the European Social Fund and the European Regional Development Fund “A Way to Build Europe.” The CNIC is supported by Ministerio de Ciencia, Innovacion y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S