Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats

Abstract

Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC–ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS.