| Popis: |
Lipid oxidation and its products are extremely important for various physiological and pathological processes, including age-related macular degeneration, atherosclerosis, immune response, and tumor development. (2-(ω-carboxyehtyl)pyrrole (CEP), which is produced under hyper-oxidative conditions of DHA is an especially crucial inducer and stimulator for the process of AMD disease development. Our data indicate that CEP adducts are generated during inflammation and wound healing processes. CEP products accumulate at high levels in aging tissues and in highly vascularized tumors such as melanoma. The molecular mechanism of CEP promotion of angiogenesis is shown to be mediated by the Toll-like receptor 2 (TLR2) and it is distinguished from the classical vascular endothelial growth factor (VEGF) pathway. It is notable that CEP is recognized by TLR2/TLR1 but not TLR2/TLR6 heterodimers on endothelial cells through the MyD88 adaptor. Similarly, 4-oxoheptanedioic acid amide (OH-diA), an alternative product of DHA oxidation, also induces angiogenesis via the TLR2 pathway. In contrast to CEP and OH-diA, 2-ethypyrrole (EP) is not pro-angiogenic. Thus, oxidation of DHA might give rise to both pro-angiogenic and non-angiogenic metabolites. Highly vascularized tumors including melanoma accumulate high levels of the angiogenic CEP protein modification, whereas, in contrast, tumors with a lower degree of vascularization, such as ovarian or prostate tumors, accumulate the nonangiogenic EP protein modification. Furthermore, 2-(ω-carboxyheptyl)pyrrole (CHP), which is generated from linoleic or linolenic acid, is also non angiogenic, and is present in various types of tumors without any correlations with the levels of vascularization. In addition, evidence was obtained demonstrating that the length of carboxyalkyl chain affects the response to CAPs in the tubulogenesis assay. The angiogenic acitivity of arachidonic acid-derived CAP analogs, protein derivatives of levuglandin (LG) E2 and iso[4]LGE2, were examined. Only the latter is angiogenic. Thus, protein modifications derived from oxidized lipids may exhibit different levels of activity on vasculargenesis, emphasizing the regulatory role of lipid metabolism and oxidation in human pathophysiology. The summation of these findings provides a fundamental mechanistic basis for understanding the pathological consequences of lipid oxidation. |
