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SHR Neuro Cancer Cardio Metab Microb Lipid

MPO-modified high-density lipoprotein and receptors

Abstract: The vascular endothelium is a wide spread organ responsible for the regulation of hemodynamics, angiogenic vascular remodeling, metabolic, synthetic, antiinflammatory, and antithrombogenic processes. Diminished nitric oxide (NO) availability has been linked to vascular disease and a heightened state of inflammation is characterized, in part, by an increase in vascular myeloperoxidase and proteins in vivo modified by its principal oxidant, hypochlourous acid/hypochlorous acid/hypochlorite (HOCI/OCI). Modification of high-density lipoprotein (HDL) by HOCI generates a proatherogenic and proinflammatory lipoprotein particle. HOCI-HDL, present in human lesions material and on endothelial cells, attenuates the expression and activity of vasuloprotective endothelial NO synthase (eNOS). Therefore, one part of this application is to clarify the mechanisms that governs interaction of HODI-HDL and its lipid (plasmalogen)-derived oxidant 2-chlorohexadecanal with eNOS, to focus whether caveolae-located proteins are involved, to profile alterations in endothelial gene expression patterns, and to investigate endothelium-dependent vascular relaxation in aortic rings and perfused vessels. As endothelial dysfunction may be induced by receptor-ligand interaction, the other part of this application will focus on interaction of HOCI-HDL with candidate receptors mediating (patho)physiologically relevant cellualar responses, i.e. activation of transcription factors, kinases and production of cytokines, leadng to the perpetuation of the inflammatory response and endothelial dysfunction. To answer these questions cell lines overexpressing candidate receptors will be used before adapting the cellular signaling cascade patterns to a specific endothelial cell line. We propose that myeloperoxidase-modified HDL- a unique and clinically significant marker for atherosclerosis - mediates endothelial dysfunction by specific receptor-evoked intracellular signaling pathways.

Keywords: medical biochemistry; medical molecular biology; radiotherapy; (High-density) lipoprotein; Hypochlorite; Hypochlorous acid; Myeloperoxidase; NO biosynthesis; Scavenger Receptors

Project Leader:: Malle Ernst

Duration:: 16.12.2006-15.12.2011

Programme:: Einzelprojekt

Type of Research: basic research

Staff: Malle, Ernst, Project Leader

MUG Research Units: Division of Molecular Biology and Biochemistry

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

Project results published: > Targeted subendothelial matrix oxidation by myelop... Free Radic Biol Med. 2012; 53(12):2344-2356; > LPA-induced suppression of periostin in human oste... Biochimie. 2012; 94(9):1997-2005; > Phloretin ameliorates 2-chlorohexadecanal-mediated... Free Radic Biol Med. 2012; 53(9):1770-1781; > Neutrophil-cytokine interactions in a rat model of... TOXICOLOGY. 2011; 290(2-3): 278-285.; > Hypochlorite-modified low-density lipoprotein indu... Biochem Biophys Res Commun. 2011; 410(4): 895-900.; > Hypochlorite-modified high-density lipoprotein pro... Arch Biochem Biophys. 2011; 509(1):16-25; > Peroxynitrite modifies the structure and function ... FREE RADICAL BIOL MED. 2010; 49(2): 282-293.