Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Binder, V.
Uremic Albumin blocks Reverse Cholesterol Transfer: The Role of Lysine Modifications
[ Dissertation ] Medical University of Graz; 2013. pp. 86
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- Autor*innen der Med Uni Graz:
- Binder Veronika
- Betreuer*innen:
- Marsche Gunther
- Wadsack Christian
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- Abstract:
- Neutrophils are the first line of defense against invading microorganisms and thus accumulate in high numbers at sites of tissue injury. Neutrophils contain myeloperoxidase (MPO), which is released after activation by intraluminal degranulation. MPO catalyzes the production of reactive chlorinating species like the powerful oxidant hypochlorous acid (HOCl). HOCl modifies proteins by various ways, including conversion of cysteine residues to disulfides and higher oxidation products, conversion of methionine residues to methionine sulfoxides, oxidation of tryptophan and chlorination of amino groups and tyrosine. Reaction of chlorinated oxidants with plasma albumin, leads to formation of advanced oxidation protein products (AOPPs). Recent findings revealed that AOPPs are inhibitors of the major high-density lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI), blocking HDL association and reverse cholesterol transport (RCT). Dramatically elevated plasma levels of AOPPs are observed in patients suffering from renal failure, a disease associated with persistent inflammation. Accordingly, albumin isolated from end stage renal disease (ESRD) patients on hemodialysis (HD), but not albumin isolated from healthy controls, markedly inhibits HDL association to SR-BI, indicating that an oxidized fraction of albumin present in uremic blood is recognized by the receptor. In this thesis project, we demonstrate that the myeloperoxidase product HOCl generates SR-BI inhibitors that irreversibly block the receptor. Our data show that already mild oxidation of albumin generates high affinity ligands to SR-BI that effectively displace HDL from SR-BI and block SR-BI mediated selective lipid uptake. We observed that oxidation/modification of lysine residues is essential for binding of albumin to SR-BI since masking lysine residues prior to oxidation as well as regeneration of lysine oxidation products completely averted binding. In this regard, alterations in the specific charge distribution caused by neutralization of positively charged ¿-amino groups of lysine residues through oxidation or carbamylation are most probably decisive for the transformation of albumin into an SR-BI ligand. We found striking evidence that HOCl-albumin mediated blockade of SR-BI and impairment of RCT are a consequence of irreversible association of HOCl-albumin to the receptor which is promoted by N-chloramines within the oxidized protein. Displacement of HDL from its major receptor results in decreased hepatic cholesterol uptake, depressed HDL metabolism and abnormal HDL composition and function. We observed that the SR-BI inhibitory activity of albumin isolated from chronic kidney disease (CKD) patients correlated with the content of the myeloperoxidase-specific oxidation product 3-chlorotyrosine (3-CT) and was associated with alterations in the composition of HDL. The present results raise the possibility that MPO-catalyzed oxidative protein damage is an important component in the pathophysiology of uremia. Impaired reverse cholesterol transfer disables HDL metabolism and directly entails compositional and functional alterations of HDL.