Proteins lose their nitric oxide stabilizing function after advanced glycosylation.
In vivo generated nitric oxide, NO, circulates in plasma mainly as an S-nitroso adduct of serum albumin. Compared to free NO, this NO-adduct is relatively long-lived. It exerts EDRF-like effects of vasodilation and platelet inhibition. Free NO is directly inactivated ('quenched') by advanced glycosylation end products (AGEs), glucose-derived protein moieties that form nonenzymatically and accumulate primarily on long-lived tissue proteins. They have been implicated in many of the long-term complications of diabetes mellitus. We found that the antiproliferative effects of thiol-stabilized NO (SNO-BSA) on Con A-stimulated lymphocytes from peripheral blood were even stronger than those of the NO-generating drug SNAP. The antimitogenic activity of SNO-BSA, however, was not significantly enhanced by the low molecular weight NO-carrier glutathione. NO liberated from SNO-BSA in molar excess was almost completely quenched by AGE-BSA. NO-dependent activating effects such as enhanced rate of glucose uptake or generation of cGMP in resting peripheral mononuclear cells (PBMC) and the antiproliferative activity of the NO-carrier BSA on Con A-stimulated cells were thereby abolished. In contrast, advanced glycosylation impaired the ability of BSA to function as NO-carrier, as evidenced by the lack of antiproliferative activity of NO-AGE-BSA and its inability to activate glucose transport or cGMP generation.
Institute of Immunology, University of Vienna, Austria.
J
J
Farkas
E J
EJ
Menzel
D001798:Blood Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D001798:Blood Proteins; D014665:Vasodilator Agents; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; D005947:Glucose