Atherogenesis and plaque rupture, surface/interface-related phenomena

In atherogenesis, free oxygen radicals cause a lipid peroxidation of apoB100-containing lipoproteins in the blood, at the blood–endothelium-interface and in the subendothelial space. These lipoproteins easily aggregate, bind to their receptor heparan sulfate proteoglycan and calcify to arteriosclerotic nanoplaques (ternary complexes). Nanoplaque formation was measured by ellipsometry, both in vitro on an HS-PG coated hydrophobic silica surface and also in vivo on living human coronary endothelial cells, which had overgrown the silica surface. Reversely, we show with the same techniques that, in dependence on the degree of peroxidation and epitope in concern, oxLDL attacks its molecular receptor and thus can induce degradation of arteriosclerotic plaques and, in a combined action with inflammatory processes, even a plaque rupture. In order to delay or stop this process, cytokines circulating in the blood such as TNFα and TGFβ upregulate PML-NB especially in the vulnerable shoulder region of the plaque. PML-NB influences via two transcription factors, CIITA and NFκB, the collagen and proteoglycan synthesis both negatively and positively. We could prove that the purely negative effect of CIITA does not play any role, while the altogether positive effect of NFκB predominates. NFκB is inhibited with the help of the transcription mediator SMAD4 within this molecular feedback control circuit; simultaneously, NFκB inhibits the collagen and proteoglycan synthesis in the fibrous cap of the plaque. This double check (disinhibition) causes a stabilization of the fibrous cap through a specially strong collagen and proteoglycan production, which in addition is supported by circulating TGFβ. TGFβ furthers also calcification, so that fibrous cap tensile strength and resistance to shear stress are imparted. This way, a plaque rupture can possibly be averted