Stites Wesley E, Froude Jeffrey W
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701-1201, United States.
Med Hypotheses. 2007;68(4):811-21. doi: 10.1016/j.mehy.2006.09.009. Epub 2006 Oct 24.
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.
吸烟者过早死亡的主要原因是心血管疾病。糖尿病患者也易患心血管疾病，且发病率有所增加。部分原因是这些病症会导致血液高凝状态。然而，吸烟者和糖尿病患者心血管疾病风险升高以及血栓前状态的分子原因仍不清楚。众所周知，这两种情况下氧化应激都会增加。在吸烟者中，已证实肺部α1-抗胰蛋白酶中的甲硫氨酸残基会发生氧化，进而导致肺气肿。血栓调节蛋白是血液凝固的关键调节因子，存在于内皮细胞上。已知血栓调节蛋白中甲硫氨酸388的氧化会减缓血栓调节蛋白-凝血酶复合物激活蛋白C的速度，而蛋白C反过来会降解激活凝血酶并导致血栓形成的因子。与肺气肿的病因类似，据推测，相对于不吸烟者，吸烟者以及可能在诸如糖尿病等给身体带来氧化应激的病症中，这种甲硫氨酸的氧化会增加。本文提供了证据来支持这样一种假设，即这种氧化以及随之而来的活化蛋白C水平降低会导致心血管疾病风险升高。
