Acrolein is a toxin which can be produced endogenously, obtained from the diet, or organisms can be exposed to it in their environment. Because of the multiple routes of exposure and its high level of toxicity, there have been many studies which have looked at the mechanisms of acrolein-induced toxicity (Stevens and Maier 8). There have been several studies which have focused on the effects of acrolein on the cardiovascular system as previous research has implicated acrolein exposure as a potential cause of cardiovascular disease (Henning et al. 230). Furthermore, research shows that acrolein can cause increases in calcium which promotes NF kappa B activation in kidney epithelial cells, which leads to toxicity (Kehrer and Biswall 10). However, the specific mechanisms associated with acrolein-induced toxicity within the cardiovascular system, and also the kidney, have yet to be fully elucidated (Dejarnett et al 1).

There are many different mechanisms which have been proposed to explain the regulation of acrolein toxicity in different tissues. For example, in vascular tissue, it has been suggested that altered vascular constriction and dilation may be the result of reduced nitric oxide production due to the presence of increased oxidative stress (Yousefipour et al. 350). Previously, research has shown that two of the players in acrolein-induced toxicity is that of oxidative stress and inflammation (Moghe et al. 244). While there are many potential upstream regulators of both oxidative stress and inflammation, one regulator which has been implicated in acrolein-induced toxicity it that of peroxisome proliferator-activated receptor gamma, PPARγ (Moghe et al. 249). PPARγ is a member of the PPAR family and is a transcription factor which is activated by the presence of specific ligands. It plays a role as a regulator in many different pathways including inflammation, oxidative stress, and lipid metabolism (Polvani et al. 4). PPARγ has also been linked to the modulation of cardiac metabolism and mitochondrial function (Lee et al. 3).

Coinciding with the above-stated information, previous research has found that treatment with acrolein significantly reduced PPARγ activity within the liver which corresponded to an increase in chemokine activity. Treatment with GW1929, a PPARγ ligand, significantly reduced this increase in chemokine activity. With respect to oxidative stress, treatment with acrolein significantly reduced antioxidant status and increased oxidative stress. However, this effect was reversed by the addition of GW1929, indicating the important role of PPARγ in the prevention of the toxic effects observed after acrolein exposure (Yousefipour et al. 489). Oxidative stress is an important determinant of cellular death, with high levels of oxidative stress leading to the activation of cell death pathways.

Interestingly, PPARγ has also been independently linked to the development of heart disease (Chandra et al. 3). Therefore, this indicates that the increased risk of development of heart disease observed after acrolein exposure may be mediated through the PPARγ pathway. However, while acrolein toxicity in other organs, such as the rat kidney, has been investigated the role of PPARγ remains underappreciated. For example, within the rat kidney, it was found that the major mechanisms of acrolein toxicity are that of formation of a GSH-acrolein adduct which leads to the occurrence of cellular damage (Horvath et al. 205). In a separate study of heart dysfunction, it was found that increased activation of PPARγ in LPS-treated mice prevented the occurrence of cardiac dysfunction, and this was unrelated to the occurrence of inflammation and corresponded to alterations in the level of autophagy (Drosatos et al. 2).

Another major player in acrolein-induced toxicity is that of autophagy. Autography is a process in which cells are degraded and recycled into their specific cellular components. There are many different forms of autophagy, such as mitophagy, but in general, the term applies to any cellular process which results in the destruction and recycling of a cellular component. In low levels, autophagy is beneficial and can prevent the occurrence of cellular death. However, in higher levels, autophagy can result in the increased occurrence of cell death (Yonekawa et at. 107).

Previously, it was found that in the lungs, treatment with acrolein led to the occurrence of mitochondrial fission which then caused the occurrence of a specific form of autophagy known as mitophagy. However, treatment of cells with an inhibitor of autophagy (chloroquine) or an inducer of autophagy (rapamycin) did not alter the level of toxicity in cells treated with acrolein (Wang et al. 70413). Therefore, while there was an increase in autophagy, this was not a determinant of the toxic effect of acrolein. As acrolein causes significant damage to mitochondria, these results indicate that mitophagy is not sufficient to remove the damaged mitochondria in acrolein-induced toxicity (Wang et al. 70408). As no specific studies on the link between autophagy and acrolein toxicity in the heart or the kidney could be located, more research is necessary in order to fully understand the role of autophagy in acrolein-induced toxicity.

While not directly related to acrolein toxicity, a previous study, on obesity-induced kidney diseases, has shown that deficiency of p62, which is involved in autophagy significantly increases PPARγ levels (Satriano and Sharma 32). While there are several other studies in different tissues, none have focused on the interrelationship between PPARγ and autophagy in the cardiovascular system. Further, no specific studies on autophagy in the rat kidney were found. Therefore, it appears that most of the research on the cardiovascular system and acrolein toxicity is focused on the development of heart disease. Based on this previous body of research, it appears that these two specific pathways are indeed interrelated and are both likely involved in the regulation and modulation of acrolein-induced cellular toxicity. However, more work is needed to determine if these effects occur in acrolein-induced toxicity.