Does the oxidation of methionine in thrombomodulin contribute to the hypercoaguable state of smokers and diabetics?

Abstract

The leading cause of premature death in smokers is cardiovascular disease. Diabetics also suffer from increased cardiovascular disease. This results, in part, from the hypercoagulable state associated with these conditions. However, the molecular cause(s) of the elevated risk of cardiovascular disease and the prothrombotic state of smokers and diabetics remain unknown. It is well known that oxidative stress is increased in both conditions. In smokers, it is established that oxidation of methionine residues takes place in α 1 -antitrypsin in lungs and that this leads to emphysema. Thrombomodulin is a key regulator of blood clotting and is found on the endothelium. Oxidation of methionine 388 in thrombomodulin is known to slow the rate at which the thrombomodulin-thrombin complex activates protein C, a protein which, in turn, degrades the factors which activate thrombin and lead to clot formation. In analogy to the cause of emphysema, it is hypothesized that oxidation of this methionine is elevated in smokers relative to non-smokers and, perhaps, in conditions such as diabetes that impose oxidative stress on the body. Evidence for the hypothesis that such an oxidation and concomitant reduction in activated protein C levels would lead to elevated cardiovascular risk is presented.

Preoperative smoking is associated with early graft failure after infrainguinal bypass surgery

“…11,13,26,29,30 In addition, methionine-oxidation on thrombomodulin can also lead to a prothrombotic state seen in smokers. 31 It is possible that persistent cigarette smoke exposure preoperatively predisposes a patient to graft failure soon after surgery. It is unclear exactly how long cigarette toxins remain in the circulation.…”

Effects of chronic cigarette smoking on endothelial function in young men

“…Although TM levels in plasma were not significantly different between smokers and non-smokers, TM levels correlated with FMD among all subjects (smokers and non-smokers) in this study. As correlations between TM and several biochemical markers of endothelial dysfunction have been indicated [44], TM, as well as its oxidative modification, would be regarded as useful biomarkers for cigarette smoking [45].…”

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

“…Other oxidative stress conditions like smoking and diabetes are known to reduce the activity of TM by oxidation of its specific residue, Met388 [102]. Met388 is located on the fifth EGF domain of TM and its oxidation leads to reduced activation of protein C by thrombin in complex with the Met388 oxidized TM [103].…”