OBJECTIVES: Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. RESULTS: Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. CONCLUSIONS: These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis.