P484The inhibition of lysyl oxidase improves the cardiovascular remodeling associated with obesity in rats

Abstract

Purpose: We have previously reported that leptin can participate in the cardiovascular fibrosis associated with obesity. One of the key steps in the synthesis and maturation of the ECM involves the enzyme lysyl oxidase (LOX), which allows the crosslinking of collagen and elastin fibers and the formation of a stable and insoluble ECM. Therefore, we explore the effects of an inhibitor of LOX activity, beta-aminopropionitrile (BAPN), on cardiovascular alterations in a model of diet-induced obesity in rats, and whether or not these effects could involve the modulation of the profibrotic effects of leptin. Methods and Results: Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group were treated with BAPN (100 mg·kg-1 ·day-1) in drinking water. The inhibition of LOX prevented the increase in body weight observed in the HFD group (p<0.05). No differences were found in echocardiographic parameters of cardiac structure and systolic function among any group. As compared with CT animals, HFD rats showed an increase in relative heart weight and thickening of aorta. HFD rats showed cardiac and vascular fibrosis (picrosirius red staining), and an increase in superoxide anion (O2.-) production as evaluated by dihydroethidium staining. Inhibition of LOX reduced the production of both O2.- and collagen, especially the non-soluble one. Cardiac levels of collagen I and TGF-β were higher in HFD than in controls, while in the aorta, HFD showed high levels of collagen I, fibronectin, TGF-β and CTGF. All of these effects were prevented by the inhibition of LOX activity except the cardiac increase in cardiac galectin-3 levels. The inhibition of LOX reduced the increase in circulating leptin levels in HFD. Leptin (100 ng/ml) increased protein levels of collagen I, TGF-β and CTGF and enhanced O2.- production in both cardiac myofibroblasts and VSMCs. Leptin was also able to increase fibronectin in VSMCs. These effects were prevented by the presence of BAPN (250 μmol/L) in the culture media. Conclusions: LOX inhibition modulates the profibrotic effect of leptin in cardiac and vascular cells through the inhibition of TGF-β. BAPN improves the altered ECM by reducing collagen synthesis and limits the induction of oxidative stress observed in both myocardium and aorta of obese animals.