Obesity is associated with cardiac functional and structural alterations that seem to be consequence, at least in part, by the accumulation of adipose tissue in the heart . Recent studies have demostrated that plasma leptin concentrations, increased in several cardiac pathologies, may represent a predictor of first myocardial infarction and that leptin may represent an independent risk factor for the development of ischemic heart disease. However, cardiac effects of this hormone, that is locally produced in the heart, is not well established because it has been described both deleterious and protective effects on cardiac function and structure. For this propose, our aim was to evaluate the effects of leptin on fibrosis, oxidative stress and proliferation of cardiac fibroblasts, as well the mechanisms involved.Methods
Collagen I protein levels were measured in response to leptin (10-100 ng/ml) in cardiac fibroblats from adult rats (passage 2-3) by Western Blot. Protein expression of GTGF, TGF-β and galectin 3, profibrotic factors, was also studied in response to leptin. The proliferative response of cardiac fibroblats to leptin in the presence or not of angiotensin II (10-7M) was also evaluated by a MTT asssay. In addition, the prooxidant effect of leptin was studied by measuring superoxide anion production with DHE. Finally, the profibrotic effect of leptin was also evaluated in the presence of the antioxidant agent, melatonin (10-6 M).Results
Leptin increased (p < 0.05) superoxide anions and collagen I levels in a dose-dependent manner, reaching maximal values at 24 hours. High levels of collagen I were accompained by an increase in CTGF, TGF-β and galectin-3 production (p < 0.05), with maximum levels being reached between 6-12 hours. The presence of leptin was unable to induce proliferation of cardiac fibroblasts even at doses found in obese subjects. Moreover, leptin was unable to modify the proliferation induced by other proliferative agents such as angiotensin II. The presence of melatonin (10-6 M) was able to prevent the increase in collagen I production in these cells.Conclusions
These results suggest that leptin acts as a profibrotic factor on cardiac fibroblasts, although it was unable to modify the proliferation of these cells. The fibrotic effect seems mediated by its ability to increase oxidative stress and seems to be mediated by the activation of growth factors such as CTGF, TGF-β but also by the production of galectin-3.