Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor

Ma, J; Wan, J; Meng, J; Banerjee, S; Ramakrishnan, S; Roy, S

Autophagy has been shown to engage in a complex interplay with apoptosis in both physiological and pathological settings. Autophagy can serve as a cell survival pathway in some cellular settings by suppressing apoptosis, and in other settings, it can lead to programmed cell death, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. 39 It has been reported that suppression of autophagy precipitated neuronal cell death following low doses of METH. 1 To evaluate the protective or the detrimental role of autophagy by METH in endothelial cells, we determined cell death (Figure 5a ) in HUVECs for up to 72 h. Our results showed an increase in cell death in the presence of 3-MA, an inhibitor of class III PI3k activity widely used to inhibit autophagy. KOR antagonist and MEK1 inhibitor also accelerated METH-induced apoptosis, suggesting that the early autophagic response is a survival mechanism for endothelial cells and were mediated through the KOR ( Figure 6 ). These results help to rule out that autophagy represents a detrimental mechanism. More importantly, our data emphasize that autophagy is an early response to METH-induced stress and may have a protective role in cell death.