Acrolein, which is a highly reactive alpha,beta-unsaturated
aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated
aldehydes play an important role in the pathogenesis of a number of human diseases such as
Alzheimer's disease,
atherosclerosis and diabetes.
Acrolein is a highly ubiquitous toxic
environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in
acrolein toxicity at the cellular and molecular levels.
Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether
mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by
acrolein. Our findings show that
acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family
kinases, including ERK and p38
kinase, and the
transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to
acrolein. Phosphorylation of ERK and p38
kinases and their blockade by an ERK inhibitor,
U0126, or a p38 inhibitor,
SB203580, respectively, suggested that activation of apoptosis by
acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited
chromatin condensation,
caspase-7 and -9 activation as well as ICAD cleavage induced by
acrolein. JNK and AKT
kinases seem to be implicated in survival pathways against
acrolein insult, since their respective inhibitors,
SP600125 and
LY294002/
Wortmannin switched the mode of cell death from apoptosis to total
necrosis. Finally,
acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and
Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in
acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to
acrolein.