期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 92, 期 -, 页码 96-104出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.01.012
关键词
Fibrosis; Leptin; Lysyl oxidase; Obesity
资金
- Red de Investigation Cardiovascular [RD12/0042/0033, RD12/0042/0053]
- Miguel Servet Programme from ISCIII [CP13/00221]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Plan Estatal I + D + I [PI12/01729, PI12/01952]
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). beta-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 (O-2(center dot-)), collagen I and transforming growth factor beta (TGF-beta) 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-beta and CTGF, Akt phosphorylation and O-2(center dot-) 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. (C) 2016 Elsevier Ltd. All rights reserved.
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