Macrophage Activation and AP-1 in Atherosclerosis

High levels of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) have been identified as independent risk factors for coronary heart disease. Hypertriglyceridemia is generally associated with an increased expression of inflammatory makers and inflammation is thought to contribute to atherosclerosis and its complications. The present investigation was aimed at providing further information on the effect of native VLDL and fatty acids on inflammation and regulation of gene expression. According to our data, VLDL strongly potentiated lipopolysaccharide (LPS)-induced expression of TNF mRNA and secretion of TNF protein in human monocyte-derived macrophages. VLDL activated mitogen-activated protein kinase-ERK kinase 1/2 (MEK1/2) and activator protein-1 (AP-1), and potentiated LPS-induced activation of AP-1 and MEK1/2. Furthermore, VLDL induced caspase-1 activation, IL-1b release and IL-1b mRNA expression in macrophages. A mixture of fatty acids stimulated TNF secretion and increased TNF mRNA expression. This was associated with activation of transcription factors nuclear factor-kB (NF-kB) and AP-1. These findings demonstrate that VLDL and fatty acids can promote inflammation. In addition, human carotid plaques associated with symptoms were characterized by increased AP-1 activity as compared to asymptomatic plaques. AP-1 activity correlated with cholesteryl ester and elastin content of the plaques. High serum triglycerides and elevated free fatty acids are associated with diabetes. On the other hand, the major cause of morbidity and mortality in patients with type 2 diabetes is coronary heart disease. Thus our results suggest that the inflammatory response induced by VLDL and fatty acids could be a link between atherosclerosis and diabetes.