Abstract 326: Cd36 Deficiency Reduces Obesity-associated Inflammation And Oxidative Stress In Heart

Abstract

OBJECTIVE: Obesity is often associated with diabetes and cardiovascular diseases (CVD). Mounting evidence shows that diabetes is associated with structural and functional changes in the heart. CD36 protein is highly expressed in heart and regulates lipid utilization in cardiacmyocytes. In this paper, we investigated the impact of CD36 expression on obesity-associated inflammation and oxidative stress in heart. METHODS: Studies were conducted in control lean (WT), obese leptin deficient (Lep Ob/Ob ) and leptin deficient-CD36 null (Lep Ob/Ob -CD36 -/- ) mice. To examine obesity-associated insulin resistance, glucose uptake and insulin signaling were examined in adult mouse hearts. Presence of macrophages in heart was examined with immunohistochemisty. Oxidative stress makers and activity of anti-oxidant enzymes were measured in hearts. To evaluate substrate utilization, glucose and fatty acid oxidation was tested in primary cultures of ventricular myocytes. Finally, the activity of pro-inflammatory kinases p38 mitogen-activated protein kinases (p38-MAPK), c-Jun NH2-terminal kinases (JNK) were examined in cardiacmyocytes challenged with palmitate. RESULTS: In Lep Ob/Ob , glucose uptake and oxidation in heart was lower than lean WT mice, while cardiac FA oxidation was strongly higher. Silencing CD36 in Lep Ob/Ob mouse markedly improved insulin sensitivity and glucose uptake in heart, but resulted in marked reduction of FA oxidation. Immunostaining of heart sections with macrophage specific antibody F4/80 showed that macrophage content was higher in myocardium of Lep Ob/Ob mice than Lep Ob/Ob -CD36 -/- mice. Moreover, oxidative stress markers, isoprostanes and reactive oxygen species, and expression of pro-inflammatory cytokines were higher in hearts of Lep Ob/Ob than Lep Ob/Ob -CD36-/- mice, although the activities of anti-oxidant enzymes were comparable. Chronic overload of Lep Ob/Ob cardiac myocyte with palmitate strongly induced the activity of JNK and p38-MAPK, but was less effective in Lep Ob/Ob -CD36 -/- cardiac myocytes. CONCLUSIONS: These results show that CD36 deficiency induced a significant reduction of obesity-associated oxidative stress and inflammation in heart in parallel to a drop in fatty acid oxidation.