Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

S100A12 is a member of the S100 family of EF-hand calcium-binding proteins. Besides calcium binding S100A12 also shows high affinity for zinc and copper ions. Extracellular S100A12 is predominantly secreted by granulocytes and monocytes and is part of the innate immune response.
S100A12 is markedly overexpressed in inflammatory compartments, and elevated serum levels of S100A12 are found in patients suffering from various inflammatory and metabolic disorders. In this regard, binding of copper by S100A12 is assumed to play a pathogenic role. In vitro experiments show that copper-bound S100A12 can function as a pro-oxidant agent by supporting both copper reduction and copper redox-cycling, respectively. As a consequence, copper-bound S100A12 enhances and accelerates oxidation of human low density lipoprotein lipids and apolipoproteins, respectively. Furthermore, copper-bound S100A12 stimulates proinflammatory activation of endothelial cells, granulocytes, and monocytes. These processes were substantially suppressed in the presence of redox-inert copper-chelating or radical-scavenging agents. Clinical examinations show significantly elevated plasma S100A12 levels in subjects with impaired glucose tolerance, newly-diagnosed diabetes mellitus Type 2, and acute rheumatoid arthritis (1.5 to 3-fold higher than in control subjects). In the patient groups, plasma S100A12 is strongly associated with plasma markers of both LDL oxidation and inflammation, and, additionally, with ultrasonically measured carotid atherosclerosis. It is suggested that oxidation processes mediated by copper-bound S100A12 are involved in accelerated atherogenesis in proinflammatory states.
Supported by Deutsche Forschungsgemeinschaft (Pi 304/1-1)