Background: Associations between cardiovascular diseases and mercury have been frequently described, but underlying mechanisms are poorly understood. Objectives: We investigate the procoagulant activation of erythrocytes, an important contributor to thrombosis, by low-level mercury to explore the roles of erythrocytes in mercury-related cardiovascular diseases. Methods: We used freshly isolated human erythrocytes and ex vivo and in vivo thrombosis models in rats to investigate mercury-induced procoagulant activity. Results: Prolonged exposure to low-dose mercuric ion (Hg2+; 0.25-5 μM for 1-48 hr) induced erythrocyte shape changes from discocytes to echinocytes to spherocytes, accompanied by microvesicle (MV) generation. These MVs and remnant erythrocytes expressed phosphatidylserine (PS), an important mediator of procoagulant activation. Hg2+ inhibited flippase, an enzyme that recovers PS into the inner leaflet of the cell membrane, and activated scramblase, an enzyme that alters lipid asymmetry in the cell membrane. Consistent with these activity changes, Hg2+ increased intracellular calcium and depleted ATP and protein thiol. A thiol supplement reversed Hg2+-induced MV generation and PS exposure and inhibited the increase in calcium ion (Ca2+) and depletion of ATP, indicating that free-thiol depletion was critical to Hg2+-mediated procoagulant activity. The procoagulant activity of Hg2+-treated erythrocytes was demonstrated by increased thrombin generation and endothelial cell adhesion. We further confirmed Hg2+-mediated procoagulant activation of erythrocytes in ex vivo and in vivo rat thrombosis models, where Hg2+ treatment (0.5-2.5 mg/kg) increased PS exposure and thrombus formation significantly. Conclusion: This study demonstrated that mercury could provoke procoagulant activity in erythrocytes through proteinthiol depletion-mediated PS exposure and MV generation, ultimately leading to enhanced thrombosis.
|Number of pages||8|
|Journal||Environmental Health Perspectives|
|State||Published - Jul 2010|
- Phosphatidylserine exposure
- Procoagulant activity