The increased phosphatidic acid (PA) and phospholipase D (PLD) activity are frequently observed in various disease states including cancers, diabetes, sepsis, and thrombosis. Previously PA has been regarded just as a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG). However, increasing evidence suggests independent biological activities of PA itself. Here we have demonstrated that PA can enhance thrombogenic activities in human erythrocytes through phosphatidylserine (PS) exposure in a calcium-dependent manner. In freshly isolated human erythrocytes, treatment of PA or PLD induced PS exposure. PA-induced PS exposure was not attenuated by inhibitors of phospholipase A2 or phosphatidate phosphatase which convert PA to LPA or DAG. Intracellular calcium increase and resultant activation of calcium-dependent protein kinase C (PKCα) appeared to underlie PA-induced PS exposure through the activation of scramblase. Marginal decrease in flippase activity was also noted, contributing further to the maintenance of exposed PS on outer membrane. PA-treated erythrocytes showed strong thrombogenic activities as demonstrated by increased thrombin generation, endothelial cell adhesion, and erythrocyte-aggregation. Importantly, these procoagulant activations by PA were confirmed in rat in vivo venous thrombosis model, where PA significantly enhanced thrombus formation. In conclusion, these results suggest that PA can induce thrombogenic activities in erythrocytes through PS exposure, which can increase thrombus formation and ultimately contribute to the development of cardiovascular diseases.
- Procoagulant activation
- Thrombus formation
- Copyright © 2009, American Journal of Physiology - Heart and Circulatory Physiology