An elevated level of LDL cholesterol is associated with the development of atherosclerosis and is also associated with aging. Modification of LDL particle is one of the main contributors to the development of atherosclerosis and is elevated with increasing plasma LDL concentrations. Modified LDL is usually composed of LOOH/aldehydes, unfolded protein and some protein post-translational modifications. It has been debated whether the lipid peroxides or unfolded apoB-100 protein is important. An important pathway in atherosclerosis may be the phosphorylation of JNK-2 in ECs. OxLDL-R CD-36 knockout macrophages which have decreased foam cell formation and decreased JNK-2 phosphorylation as well as an ApoE and JNK-2 double knockout mouse has decreased lesion size and MFC formation. Foam cells have increased ROS production and mitochondria are the major source of ROS and this evidence may suggest that p-JNK-2 is involved in regulating mitochondrial function. We hypothesize that ONOO ^- induced nitration and unfolding of apoB-100 may be a potential mechanism for modification of LDL in vivo and that this unfolded LDL induces oxLDL-R dependent irreversible mitochondrial dysfunction in ECs to promote atherosclerosis. The purpose of this study was to determine (a) where the modified fraction of LDL in vivo (LDL^-) is nitrated, (b) whether ONOO^- produces a particle with a similar nitration pattern and protein unfolding to in vivo LDL^-, (c) whether nitrotyrosine is co-localized to the bifurcation and whether OSS induces ONOO^- formation, (d) how differentially modified LDL induces JNK-2 phosphorylation, (e) what oxLDL receptors are involved in the phosphorylation of JNK-2, (f) whether phospho-JNK-2 co-localizes with mitochondria and is regulating mitochondrial function. The modified LDL fraction in vivo (LDL^-) is nitrated in alpha helices that are involved in protein unfolding. It was also determined that ONOO^- treated LDL had a similar nitration and unfolding to in vivo LDL^-. We found that human coronary artery at the bifurcation where atherosclerosis is prevalent and OF occurs were positive for nitrotyrosine and implicated ONOO^- formation by a 1:1 ratio of O2^·- and ^·NO production. Protein unfolding of LDL was the most important initiator of JNK-2 phosphorylation. Upon receptor blocking, JNK-2 phosphorylation was dependent on both CD-36 and SR-A oxLDL-R. Modified LDL dependent JNK-2 phosphorylation co-localized with mitochondria and was ablated by both SR-A and CD-36 receptor blocking antibodies but was only minimally affected by either one alone suggesting that both receptors are induce p-JNK-2 co-localization to mitochondria. Phosphorylation of Bcl-xL and caspase-3 activation was blocked by incubation with both CD-36 and SR-A receptor blocking antibodies. Human coronary arteries in diseased hearts were robustly positive for CD-36 and p-JNK-2 co-localization with mitochondria in ECs of the lumen and of the vasa vasorum as well as in macrophages, MFCs and SMCs. Our findings demonstrate that ONOO^- may be involved in the modification of LDL in vivo, that ONOO^- modified LDL was similar in structure and nitration pattern to an in vivo nitrated LDL particle and that protein unfolding is involved in the initiation of apoptosis and atherosclerosis through an oxLDL-R dependent phosphorylation of JNK-2.