Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK.

Autor: Martínez-Revelles S; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .; 2 CIBER de Enfermedades Cardiovasculares , Spain ., García-Redondo AB; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .; 2 CIBER de Enfermedades Cardiovasculares , Spain ., Avendaño MS; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain ., Varona S; 2 CIBER de Enfermedades Cardiovasculares , Spain .; 3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain ., Palao T; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain ., Orriols M; 2 CIBER de Enfermedades Cardiovasculares , Spain .; 3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain ., Roque FR; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain ., Fortuño A; 4 Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra , Pamplona, Spain ., Touyz RM; 5 Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow, United Kingdom ., Martínez-González J; 2 CIBER de Enfermedades Cardiovasculares , Spain .; 3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain ., Salaices M; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .; 2 CIBER de Enfermedades Cardiovasculares , Spain ., Rodríguez C; 2 CIBER de Enfermedades Cardiovasculares , Spain .; 3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain ., Briones AM; 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .; 2 CIBER de Enfermedades Cardiovasculares , Spain .
Jazyk: angličtina
Zdroj: Antioxidants & redox signaling [Antioxid Redox Signal] 2017 Sep 01; Vol. 27 (7), pp. 379-397. Date of Electronic Publication: 2017 Jan 30.
DOI: 10.1089/ars.2016.6642
Abstrakt: Aims: Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H 2 O 2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin.
Results: Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with β-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H 2 O 2 and O 2 .- levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H 2 O 2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice.
Innovation: We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension.
Conclusion: LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397.
Databáze: MEDLINE
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