Upregulation of NOR-1 in calcified human vascular tissues: impact on osteogenic differentiation and calcification.
Por:
Ballester-Servera C, Cañes L, Alonso J, Puertas-Umbert L, Vázquez-Sufuentes P, Taurón M, Roselló-Díez E, Marín F, Rodríguez C, Martínez-González J
Publicada:
12 feb 2024
Ahead of Print:
9 sep 2023
Resumen:
Cardiovascular calcification is a significant public health issue whose pathophysiology is not fully understood. NOR-1 regulates critical processes in cardiovascular remodeling, but its contribution to ectopic calcification is unknown. NOR-1 was overexpressed in human calcific aortic valves and calcified atherosclerotic lesions colocalizing with RUNX2, a factor essential for osteochondrogenic differentiation and calcification. NOR-1 and osteogenic markers were upregulated in calcifying human valvular interstitial cells (VICs) and human vascular smooth muscle cells (VSMCs). Gain- and loss-of-function approaches demonstrated that NOR-1 negatively modulates the expression of osteogenic genes relevant for the osteogenic transdifferentiation (RUNX2, IL-6, BMP2, and ALPL) and calcification of VICs. VSMCs from transgenic mice overexpressing NOR-1 in these cells (TgNOR-1(VSMC)) expressed lower basal levels of osteogenic genes (IL-6, BMP2, ALPL, OPN) than cells from WT littermates, and their upregulation by a high-phosphate osteogenic medium (OM) was completely prevented by NOR-1 transgenesis. Consistently, this was associated with a dramatic reduction in the calcification of both transgenic VSMCs and aortic rings from TgNOR-1(VSMC) mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9(D374Y) and a high-fat/high-cholesterol diet. Challenged-TgNOR-1(VSMC) mice exhibited decreased vascular expression of osteogenic markers, and both less atherosclerotic burden (assessed in whole aorta and lesion size in aortic arch and brachiocephalic artery) and less vascular calcification (assessed either by near-infrared fluorescence imaging or histological analysis) than WT mice. Our data indicate that NOR-1 negatively modulates the expression of genes critically involved in the osteogenic differentiation of VICs and VSMCs, thereby restraining ectopic cardiovascular calcification.
Filiaciones:
Ballester-Servera C:
Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Cañes L:
Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Alonso J:
Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Puertas-Umbert L:
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, Spain
Vázquez-Sufuentes P:
Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Taurón M:
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Departamento de Cirugía Cardíaca, Hospital de la Santa Creu i Sant Pau-Universitat Autònoma de Barcelona (HSCSP-UAB), Barcelona, Spain
Roselló-Díez E:
Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain
Departamento de Cirugía Cardíaca, Hospital de la Santa Creu i Sant Pau-Universitat Autònoma de Barcelona (HSCSP-UAB), Barcelona, Spain
Marín F:
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Departamento de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca-Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
Rodríguez C:
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
Institut de Recerca Hospital de la Santa Creu i Sant Pau (IRHSCSP), Barcelona, Spain
Martínez-González J:
Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain. Electronic address:
hybrid, All Open Access; Hybrid Gold
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