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J Hypertens. 2014 May;32(5):1104-14; discussion 1114. doi: 10.1097/HJH.0000000000000149.

Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity.

Author information

1
aDepartamento de Fisiología, Facultad de Medicina, Universidad Complutense bDepartamento de Oftalmología y Otorrinolaringología, Facultad de Psicología, Universidad Complutense cCardiology Department, Cardiovascular Institute, Hospital Clínico San Carlos dDepartamento de Farmacología, Facultad de Medicina, Universidad Autónoma, Madrid eCardiovascular Translational Research, NavarraBiomed (Miguel Servet Foundation), Pamplona, Spain *María Miana and Victoria Cachofeiro contributed equally to this study.

Abstract

OBJECTIVE:

Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity.

METHODS:

Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks.

RESULTS:

HFD animals show cardiac hypertrophy, fibrosis and an increase in O2- production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor β (TGF-β) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O2-, collagen I, galectin-3, TGF-β and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10 mmol/l) or the inhibitor of mTOR, rapamycin (10 mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10 mmol/l) reduced both collagen I and O2(*-) production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it.

CONCLUSION:

The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-β and CTGF through oxidative stress increased by activation of mTOR pathway.

PMID:
24695395
DOI:
10.1097/HJH.0000000000000149
[Indexed for MEDLINE]

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