Lysyl oxidase-dependent extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease.

Autor: 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., 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., 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., 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., 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., Fernández-Celis A; Cardiovascular Translational Research, Navarrabiomed, IdiSNA, UPNA, Hospital Universitario de Navarra (HUN), Pamplona, 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., Rodríguez-Sinovas A; CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Cardiovascular Diseases Research Group, Vall d'Hebron University Hospital and Research Institute, Barcelona, Spain., López-Andrés N; Cardiovascular Translational Research, Navarrabiomed, IdiSNA, UPNA, Hospital Universitario de Navarra (HUN), Pamplona, 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. Electronic address: crodriguezs@santpau.cat., 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: jose.martinez@iibb.csic.es.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Nov; Vol. 167, pp. 115469. Date of Electronic Publication: 2023 Sep 18.
DOI: 10.1016/j.biopha.2023.115469
Abstrakt: Extracellular matrix (ECM) is an active player in cardiovascular calcification (CVC), a major public health issue with an unmet need for effective therapies. Lysyl oxidase (LOX) conditions ECM biomechanical properties; thus, we hypothesized that LOX might impact on mineral deposition in calcific aortic valve disease (CAVD) and atherosclerosis. LOX was upregulated in calcified valves from two cohorts of CAVD patients. Strong LOX immunostaining was detected surrounding calcified foci in calcified human valves and atherosclerotic lesions colocalizing with RUNX2 on valvular interstitial cells (VICs) or vascular smooth muscle cells (VSMCs). Both LOX secretion and organized collagen deposition were enhanced in calcifying VICs exposed to osteogenic media. β-aminopropionitrile (BAPN), an inhibitor of LOX, attenuated collagen deposition and calcification. VICs seeded onto decellularized matrices from BAPN-treated VICs calcified less than cells cultured onto control scaffolds; instead, VICs exposed to conditioned media from cells over-expressing LOX or cultured onto LOX-crosslinked matrices calcified more. Atherosclerosis was induced in WT and transgenic mice that overexpress LOX in VSMC (TgLOX VSMC ) by AAV-PCSK9D374Y injection and high-fat feeding. In atherosclerosis-challenged TgLOX VSMC mice both atherosclerosis burden and calcification assessed by near-infrared fluorescence (NIRF) imaging were higher than in WT mice. These animals also exhibited larger calcified areas in atherosclerotic lesions from aortic arches and brachiocephalic arteries. Moreover, LOX transgenesis exacerbated plaque inflammation, and increased VSMC cellularity, the rate of RUNX2-positive cells and both connective tissue content and collagen cross-linking. Our findings highlight the relevance of LOX in CVC and postulate this enzyme as a potential therapeutic target for CVC.
Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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