Acrolein is an unsaturated aldehyde which recently has become to be known as being a serious environmental health hazard. There are several different ways in which humans can be exposed to acrolein, these include oral through food and drink, respiratory through inhalation of cigarette smoke or car exhaust or exposure can also occur through the skin or it can be endogenously produced through lipid peroxidation. Recently it has been proposed the Acrolein may play a role in the diseases such as Alzheimer’s, cardiovascular disease and diabetes. There have been several different mechanisms proposed to explain acrolein-induced vascular toxicity. These include reduced nitric oxide signaling, induction of reactive oxygen species (ROS production), an induction of Nrf2, IL6 and a reduction in mTOR signaling.
As an unsaturated aldehyde, acrolein can be highly reactive. Within rats, it has been shown that there are several different chemical reactions that occur in the metabolism of acrolein. The double bond of acrolein can be attacked using an epoxidation reaction. Following which this intermediate then interact with glutathione and glutathione-s-transferase producing a S-(2-Formylethyl)glutathione compound which can further metabolized into S-(2-Formylethyl)cysteine). However, the main pathway of metabolism of acrolein is that of Michael addition of glutathione to the double bond of acrolein. This intermediate is then further processed into mercapturic acid which is then excreted in the urine after the aldehyde is reduced (Parent 118).
Previous research has shown that exposure of rats to acrolein significantly increased systolic blood pressure and doubled phenylephrine stimulated vasoconstriction compared to controls. This also coincided with a reduction in the generation of cyclic guanosine 3’5’-monophosphate (cGMP). cGMP is an important signaling molecule involved in the nitric oxide signaling. After further testing, it was found that after prolonged exposure (7 days) that this decrease in cGMP also corresponded to a decrease in urinary nitrite excretion which indicates that acrolein reduces nitric oxide production (Yousefipour et al 342).
As the endothelium secretes nitric oxide to the smooth muscle to induce vasodilation, this impairment in nitric oxide synthesis, due to decreased levels of cGMP caused by exposure to acrolein, could explain the increase in systolic blood pressure and the increase in phenylephrine stimulated vasoconstriction (Van Hove et al 920). As increased constriction can lead to damage of the surrounding tissue this can explain the toxicity observed in the vasculature after prolonged exposure to acrolein. In addition, there is increased lipid hydroperoxidation and there is a significant reduction in antioxidants such as glutathione peroxidase and glutathione-S-transferase. Previous research has shown that a pro-oxidant environment can contribute to the impairment of nitric oxide signaling. This could further contribute to a decrease in vasodilation and an increase in vasoconstriction (Lee et al 7700). In addition to vasodilation alterations in nitric oxide signaling have also been implicated in the regulation of cellular apoptosis, which also could explain the mechanism of acrolein toxicity (Brüne 866). While the occurrence of increased ROS and a breakdown in nitric oxide signaling can explain some of the effects which occur, they do not fully explain acrolein-induced toxicity.
One potential regulator of the occurrence of increased ROS and decreased antioxidants is that of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 has been shown to control the expression of antioxidant responses. In addition, previous research has also shown that another potential mechanism is that of increased Nrf2 protein expression. In human A549 lung adenocarcinoma cells, exposure to acrolein led to a significant increase in Nrf2 protein expression which corresponded with increased levels of ROS and decreased levels of antioxidants. Induction of Nrf2 is a protective mechanism which corresponds with the organisms attempt to combat the toxic effects of acrolein (Tirumalai et al 32). Another protective mechanism, which is also induced by exposure to acrolein is that of inflammation.
One of the major responses to any type of foreign substance is that of an increase in the organisms inflammatory response pathways. Exposure to acrolein, besides increasing ROS production, can also lead to the occurrence of endoplasmic reticulum (ER) stress by leading to increased phosphorylation of ERK1/2, p38, and JNK. Furthermore, acrolein also activates the unfolded protein response and leads to activation of the transcription factor NF-kB. Increased protein unfolding is an indicator of toxicity. ER activates the unfolded protein response pathway to help respond to the increased levels of unfolded proteins. When the cells are unable to adequately cope with increased levels of protein unfolding the ER stress can lead to the induction of the inflammatory response. Indeed, following exposure to acrolein, there is a significant increase in TNF-alpha, IL-6 and IL-8 expression. As other inflammatory markers are not activated (including MCP-1), this indicates that the inflammatory response occurs as a result of induction of ER stress (Haberzettl et al 20).
One final mechanism of acrolein-induced toxicity could be that of alterations to the mTOR signaling pathway. mTOR is a central regulator of metabolism and is involved in nutrient and energy sensing within the cells. Furthermore, it has also been implicated in insulin signaling pathways. After exposure to acrolein, there is a significant inhibition of mTOR in aortic endothelial cells. This inhibition leads to modulation of metalloproteinase proteins which can lead to impaired angiogenesis and cause injury to the vasculature. Therefore, alterations to mTOR signaling, as a result of acrolein exposure is a clear contributor to the observed toxicity (Lemaître 545). Overall when it comes to the mechanisms of acrolein-induced vascular toxicity, there are several different pathways which have been implicated. These include increased levels of ROS and decreased antioxidant levels, which correspond to decreased nitric oxide signaling. Furthermore, activation of Nfr2 and activation of inflammatory and ER stress pathways, as well as a reduction in mTOR signaling are the current known mechanisms. However, more research is needed in order to fully elucidate the specific mechanisms and determine if there is any cross-talk occurring between these pathways.
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