Antithrombin activity is inhibited by acrolein and homocysteine thiolactone: Protection by cysteine.
Conditions in which serum or tissue acrolein levels are high (e.g.: renal failure, heavy smoking, oxidative stress) are also associated with increased thrombogenicity. Another emerging cardiovascular risk factor is homocysteine, and its derivative, homocysteine thiolactone. Antithrombin is one of the most important inhibitors of blood coagulation Since its activation by heparin binding requires critical interactions involving 3 Lys residues; we hypothesized that acrolein or homocysteine thiolactone impair antithrombin activity. When we incubated human antithrombin with increasing concentrations of acrolein (0-2 mmol/L) over a short period of time (0-4 h), a time and concentration dependent loss of activity was apparent (IC(50)=0.25 mmol/L). At 2 mmol/L, maximum inhibition (60%) is achieved at 1 h. This loss of activity was mirrored by changes in the electrophoretic pattern (homogeneity of the native antithrombin band as well as polymerization). In the same conditions, homocysteine thiolactone produces a significant, yet far less pronounced effect; acrolein being 3 times more potent than homocysteine thiolactone. When antithrombin was co-incubated with acrolein and cysteine, only less than 10% of antithrombin activity was lost. Aminoguanidine or carnosine displayed a significant yet, minor protective effect. The results suggest that in conditions where circulating or local acrolein concentrations are increased (atheroma plaque, thrombosis, sites of lipoperoxidation, smokers), acrolein-mediated loss of antithrombin activity could be a plausible phenomenon. This could contribute to explain increased thrombogenicity in smokers and in other conditions, as well as pointing at dietary intervention or the use of thiol-conserving reducing compounds as putative coadjuvant therapeutic measures.
Gugliucci
Alejandro
A
Glycation, Oxidation and Disease Laboratory, Division of Basic Medical Sciences, Touro University-California, Mare Island Building H-83, 1310, Johnson Lane, Vallejo, CA 94592, USA. agugliuc@touro.edu
D000171:Acrolein / Q000494:pharmacology*; D000991:Antithrombins / Q000187:drug effects*; D003545:Cysteine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D010958:Plasminogen / Q000187:drug effects; D013997:Time Factors
D000991:Antithrombins; D006710:Homocysteine; D000171:Acrolein; D010958:Plasminogen; C007957:homocysteine thiolactone; D003545:Cysteine