title: The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats.
abstract: Lysyl oxidase (LOX) is an extracellular matrix (ECM)-modifying enzyme that has been involved in cardiovascular remodeling. We explore the impact of LOX inhibition in ECM alterations induced by obesity in the cardiovascular system. LOX is overexpressed in the heart and aorta from rats fed a high-fat diet (HFD). β-Aminopropionitrile (BAPN), an inhibitor of LOX activity, significantly attenuated the increase in body weight and cardiac hypertrophy observed in HFD rats. No significant differences were found in cardiac function or blood pressure among any group. However, HFD rats showed cardiac and vascular fibrosis and enhanced levels of superoxide anion (O2(-)), collagen I and transforming growth factor β (TGF-β) in heart and aorta and connective tissue growth factor (CTGF) in aorta, effects that were attenuated by LOX inhibition. Interestingly, BAPN also prevented the increase in circulating leptin levels detected in HFD fed animals. Leptin increased protein levels of collagen I, TGF-β and CTGF, Akt phosphorylation and O2(-) production in both cardiac myofibroblasts and vascular smooth muscle cells in culture, while LOX inhibition ameliorated these alterations. LOX knockdown also attenuated leptin-induced collagen I production in cardiovascular cells. Our findings indicate that LOX inhibition attenuates the fibrosis and the oxidative stress induced by a HFD on the cardiovascular system. The reduction of leptin levels by BAPN in vivo and the ability of this compound to inhibit leptin-induced profibrotic mediators and ROS production in cardiac and vascular cells suggest that interactions between leptin and LOX regulate downstream events responsible for myocardial and vascular fibrosis in obesity.
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Miana
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Jurado-López
authors.affiliation: Department of Ophthalmology and Oto-Rhino-Laringology, Faculty of Psychology, Universidad Complutense, Madrid, Spain.
authors.forename: María Visitación
authors.initials: MV
authors.lastname: Bartolomé
authors.affiliation: Cardiology Department, Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Luaces
authors.affiliation: Cardiology Department, Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Fabián
authors.initials: F
authors.lastname: Islas
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: Cardiovascular Translational Research, Navarrabiomed (Fundación Miguel Servet), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: López-Andrés
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. Electronic address: vcara@ucm.es.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cachofeiro
mesh_terms: D000629:Aminopropionitrile / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D059305:Diet, High-Fat; D005109:Extracellular Matrix / Q000187:drug effects / Q000235:genetics; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020738:Leptin; D017382:Reactive Oxygen Species; D000629:Aminopropionitrile; D008249:Protein-Lysine 6-Oxidase
keywords: Fibrosis; Leptin; Lysyl oxidase; Obesity