Import and fate of fluorescent analogs of oxidized phospholipids in vascular smooth muscle cells

Alexandra Moumtzi, Michael Trenker, Karlheinz Flicker, Elfriede Zenzmaier, Robert Saf, and Albin Hermetter

Institute of Biochemistry, Graz University of Technology, Graz A-8010

Corresponding Author: albin.hermetter{at}tugraz.at

Lipid oxidation is now thought to be an initiating and sustaining event in atherogenesis. Oxidatively fragmented phospholipids, namely 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), present in minimally modified low density lipoprotein (LDL) and atherosclerotic lesions, have been reported to elicit a wide range of pathophysiological responses in the cells of the vascular wall. Nevertheless, the question of their potential sites of action and their primary molecular targets remains open. To address this issue, a series of fluorescently labeled analogs, which differ with regard to structure and binding site of the fluorophore, were synthesized and utilized as tools for studying the uptake, intracellular stability and distribution of PGPC and POVPC in vascular smooth muscle cells (VSMC). We demonstrate that in accordance with their lysophospholipid-like structure these highly similar molecules transferred rapidly either from aqueous phospholipid dispersions or preloaded native LDL into VSMC, but produced disparate fluorescence patterns irrespective of the attached fluorophore. PGPC derivatives were translocated to the lysosomes. In sharp contrast, POVPC analogs were initially captured in the plasma membrane most likely in consequence of the formation of covalent adducts with free amino and sulfhydryl groups of proteins and phospholipids. LDL internalization is not required for cellular lipid uptake. Collectively, our data provide evidence that oxidized phospholipids owing to their high exchangeability between lipoproteins and cell membranes may act within short time on different cellular sites in VSMC affecting various lipid and protein components through physical or chemical interactions, which might then serve as starting points of intracellular signaling.

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