Abstract 13040: Left Ventricle Dysfunction is Prevented by the Treatment With Methotrexate Carried in Lipid Nanoparticles in Lipopolysaccharide-injected Rats

Abstract

Introduction: In infectious processes, left ventricle (LV) dysfunction is often associated with dysregulation of the immune response. LDE, a lipid core nanoparticle resembling LDL, is able to concentrate in inflammatory sites. We showed that methotrexate (MTX), associated with LDE, modulated inflammation and improved cardiac function in rats with myocardial infarction Hypothesis: Investigate therapeutic effects of LDE-MTX on LV function in lipopolysaccharide (LPS)-injected rats Methods: Wistar rats were submitted to 2 injections of LPS (10mg/kg ip), with 24h interval. Animals were allocated to control group (CT, without LPS) and 3 LPS groups: LDE, treated with only LDE; MTX, with commercial MTX; and LDE-MTX. LDE-MTX dose was 1mg/kg I.P. 72h after LPS, animals were submitted to echocardiographic analysis. Animals were euthanised for analysis of the LV Results: Rats treated with LDE developed diastolic dysfunction and presented decreased diastolic volume and diameter of the LV, which was prevented by LDE-MTX. Only LDE-MTX treatment elicited cardiac hypertrophy through the increase of the thickness of LV septum and posterior wall, LV mass, relative heart weight and myocyte diameter. Inflammatory and apoptotic markers were similar in LPS groups, but LDE-MTX treatment increased macrophage recruitment (CD68). Angiogenesis, represented by vascular endothelial growth factor (VEGF), was higher in LDE-MTX compared to all other groups. Hypoxia-inducible factor 1 alpha, which was remarkably higher in LDE, was normalized by LDE-MTX to CT levels. A1, A2b and A3 adenosine receptors expression was higher in LDE-MTX, compared to CT, indicating an increase in intracellular adenosine. Myocyte diameter was positively correlated with VEGF (r2= 0.52; p<0.0001) Conclusions: The increased recruitment of immune cells to the LV indicates that treatment with LDE-MTX was effective in activating immune response, impaired by LPS. LDE-MTX increased intracellular adenosine availability, contributing to an adaptive LV hypertrophy, increase in angiogenesis and diminished cellular hypoxia. These mechanisms conceivably elicited the observed LV improvement of diastolic dysfunction caused by LPS challenge