title: Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK.
abstract: OBJECTIVE
  Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H2O2as 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 H2O2and O2.-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 H2O2scavenger 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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 .
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez-Revelles
authors.affiliation: 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 .
authors.forename: Ana B
authors.initials: AB
authors.lastname: García-Redondo
authors.affiliation: 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .
authors.forename: María S
authors.initials: MS
authors.lastname: Avendaño
authors.affiliation: 2 CIBER de Enfermedades Cardiovasculares , Spain .|3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain .
authors.forename: Saray
authors.initials: S
authors.lastname: Varona
authors.affiliation: 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .
authors.forename: Teresa
authors.initials: T
authors.lastname: Palao
authors.affiliation: 2 CIBER de Enfermedades Cardiovasculares , Spain .|3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain .
authors.forename: Mar
authors.initials: M
authors.lastname: Orriols
authors.affiliation: 1 Departamento de Farmacología, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ) , Madrid, Spain .
authors.forename: Fernanda R
authors.initials: FR
authors.lastname: Roque
authors.affiliation: 4 Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra , Pamplona, Spain .
authors.forename: Ana
authors.initials: A
authors.lastname: Fortuño
authors.affiliation: 5 Institute of Cardiovascular and Medical Sciences, University of Glasgow , Glasgow, United Kingdom .
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: 2 CIBER de Enfermedades Cardiovasculares , Spain .|3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain .
authors.forename: Jose
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: 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 .
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
authors.affiliation: 2 CIBER de Enfermedades Cardiovasculares , Spain .|3 Centro de Investigación Cardiovascular (CSIC-ICCC) , IIB-Sant Pau, Barcelona, Spain .
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: 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 .
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004549:Elastin / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D059289:Vascular Stiffness; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C077112:Lox protein, mouse; D004549:Elastin; D008249:Protein-Lysine 6-Oxidase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: NADPH oxidases; extracellular matrix; free radicals; microvascular; mitochondria; tissue repair and remodeling