Statin and endothelial cell-derived microparticles

Abstract

Thromb Haemost 2008; 100: 377–378 Microparticles (MP) are small membrane vesicles that are released from many different cell types by a process of exocytic budding of the plasma membrane (1). Because MP disseminate various bioactive effectors originating from the parent cells, they can alter vascular function and may induce biological responses involved in the vascular system (2). For example, MP can modulate coagulation via direct and indirect mechanisms. Therefore, MP concentrations are documented in almost all thrombotic diseases occurring in venous or arterial beds (3–5). Furthermore, elevated levels of MP have been found in a number of conditions associated with inflammation, cellular activation and dysfunction, angiogenesis and transport (1, 6–8). Various factors are involved in the mechanisms of endothelial cell-derived MP (EDMP) generation (9, 10). TNFα, lipopolysaccharideor oxidized low-density lipoprotein (LDL)stimulation of cultured human umbilical vein endothelial cells (HUVEC) result in an increase in the release of EDMP expressing surface tissue factor (11, 12). Several studies report the existence of EDMP generated from apoptotic endothelial cells; for example, elevation of EDMP in patients following allogeneic stem cell transplantation is associated with some transplant-related complications that include the apoptotic mechanism of endothelial cells (13–15). Furthermore, the pattern of procoagulant MP released during acute allograft rejection suggests endothelial cell activation and Fas-mediated apoptosis (16); while procoagulant MP in pulmonary arterial hypertension also show apoptotic EDMP (17). However, the clinical significance of EDMP has not been fully revealed. A high plasma cholesterol level is a risk factor for the progression of atherosclerosis and cardiovascular disease. A high plasma level of LDL cholesterol may also promote the development of atherosclerotic disease (18). Large-scale clinical trials with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have shown that lowering cholesterol levels decreases the incidence of cardiovascular events and the progression of atherosclerosis (19). Statins have additional pleiotropic effects, many of which are mediated by the vascular endothelium (20–22). These pleiotropic effects of statins, as well as their lipid lowering effects, may be responsible for the prevention of atherosclerosis. However, the distinct mechanisms of these effects of statins are poorly understood. In this issue of Thrombosis and Haemostasis, Diamant et al. (23) have partially resolved the above noted problems. They found that simvastatin promotes EDMP release during the detachment of endothelial cells undergoing apoptosis (induced by this drug), whereas the adherent cells showed no signs of simvastatin-induced apoptosis. The authors also concluded that statins improve the overall condition of the remaining vascular endothelium by facilitating detachment and EDMP release. Such a defense system of MP protects parent cells, as previously reported. The release of MP protects cells against complement-induced lysis (24). EDMP are likely to be generated to maintain endothelial homeostasis. The current view of the role of MP is changing. Freyssinet proposed that MP not only impose a potential environment threat, but may also be essential to maintain cellular homeostasis (25). Most MP in thrombotic diseases are considered to be disadvantageous because of their procoagulant and proadhesive characteristics (25, 26). However, the study by Diamant et al. (23) suggests that elevated numbers of EDMP in patients with diabetes or cardiovascular disease reflect an activated cellular mechanism to cope with the increased endothelial stress, rather than a mechanism to impose an environmental threat to other cells and tissues. Thus, their report revises our understanding about EDMP. It also suggests a new outlook for EDMP, since the detachment of endothelial cells could contribute to a better appreciation of the effect of statins on endothelial cells.