Immune Responses Aginst Aldehyde Modified Extracellular Matrix in Atherosclerosis

Sammanfattning: Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic process. Our studies provide evidence for the presence of MDA-modifications on ECM proteins during atherosclerosis. We also show that antibodies against several MDA-modified ECM proteins are present in human plasma. A prospective clinical study showed that subjects that later suffered from acute cardiovascular events had significantly lower IgG and IgM antibody levels against MDA-modified fibronectin. These epidemiological results indicate that immune responses against MDA-modified fibronectin may have protective effects in atherosclerotic disease. To investigate the functional role of immune responses against modified matrix proteins in atherosclerosis, we immunized Apoe-/- mice with two different MDA-modified matrix proteins to which we had found antibodies in human plasma. MDA-modified fibronectin immunization significantly decreased the atherosclerotic plaque development in both aorta and in subvalvular lesions, while MDA-modified laminin resulted in increased plaque development. Finally we show that injection of Alum, an adjuvant commonly used in vaccines, results in LDL oxidation and aldehyde generation at the injection site.