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

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 alpha(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.