Upregulation of NOR-1 in calcified human vascular tissues : impact on osteogenic differentiation and calcification
Ballester-Servera, Carme (Institut de Recerca Sant Pau)
Cañes Esteve, Laia (Institut d'Investigacions Biomèdiques de Barcelona)
Alonso Nieto, Judith (Institut de Recerca Sant Pau)
Puertas Umbert, Lídia (Instituto de Salud Carlos III)
Vázquez-Sufuentes, Paula (Institut de Recerca Sant Pau)
Tauron, Manel (Institut de Recerca Sant Pau)
Roselló-Díez, Elena (Institut de Recerca Sant Pau)
Marín, Francisco (Instituto Murciano de Investigación Biosanitaria)
Rodríguez, Cristina (Institut de Recerca Sant Pau)
Martínez-González, José (Institut de Recerca Sant Pau)
Universitat Autònoma de Barcelona

Fecha:	2024
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) 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 mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9 and a high-fat/high-cholesterol diet. Challenged-TgNOR-1 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.
Ayudas:	Instituto de Salud Carlos III PI21/01048 Agencia Estatal de Investigación PID2021-122509OB-I00 Ministerio de Ciencia e Innovación RTI2018-094727-B-100
Nota:	Altres ajuts: This work was supported by Sociedad Española de Arteriosclerosis (SEA-2022). C.B-S and L.P-U were supported by a FPU (Ministerio de Universidades; Spain), and PFIS fellowships, respectively.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Atherosclerosis ; Cardiovascular calcification ; NOR-1 ; Osteogenic differentiation
Publicado en:	Translational Research, Vol. 264 (february 2024) , p. 1-14, ISSN 1878-1810

DOI: 10.1016/j.trsl.2023.09.004
PMID: 37690706

14 p, 5.5 MB

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