Pathophysiological Impact of the MEK5/ERK5 Pathway in Oxidative Stress

Abstract

Oxidative stress regulates many physiological and pathological processes. Indeed, a low increase in the basal level of reactive oxygen species (ROS) is essential for various cellular functions, including signal transduction, gene expression, cell survival or death, as well as antioxidant capacity. However, if the amount of generated ROS overcomes the antioxidant capacity, excessive ROS results in cellular dysfunctions as a consequence of damage to cellular components, including DNA, lipids and proteins, and may eventually lead to cell death or carcinogenesis. Both in vitro and in vivo investigations have shown that activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway is frequently involved in oxidative stress-elicited effects. In particular, accumulating evidence identified a prominent role of this pathway in the anti-oxidative response. In this respect, activation of krüppel-like factor 2/4 and nuclear factor erythroid 2-related factor 2 emerged among the most frequent events in ERK5-mediated response to oxidative stress. This review summarizes what is known about the role of the MEK5/ERK5 pathway in the response to oxidative stress in pathophysiological contexts within the cardiovascular, respiratory, lymphohematopoietic, urinary and central nervous systems. The possible beneficial or detrimental effects exerted by the MEK5/ERK5 pathway in the above systems are also discussed.

Sphingosine 1‐phosphate elicits a ROS‐mediated proinflammatory response in human endometrial stromal cells via ERK5 activation

“…The same effects were elicited upon pretreatment with the ROS scavenger NAC (5 mM) (Figure 7D), thus providing evidence of the involvement of ROS in the S1P-induced production of the above proinflammatory cytokines. Interestingly, pharmacological inhibition of ERK5 strongly reduced the basal expression levels of the analyzed proinflammatory cytokines (Figure 7B), in line with the data shown in Figure S4 and with previous reports 40,45 and further supporting a crucial role for this MAPK in the regulation of the inflammatory response in the endometrium.…”

“…In this respect, it is worth noting that despite ERK5 inhibition almost completely S1P-induced ROS we may not exclude that activation of the SFK/MEK5/ERK5 signaling is dependent. 40,67,68 On the other hand, our data indicate that S1P-induced ERK5 activation is mediated by MEK5, in line with the well-established notion that ERK5 activation is classically operated by its upstream MAPKK, MEK5, that has ERK5 as its only known substrate. 69 To our knowledge, this is the first evidence of MEK5 activation by the bioactive sphingolipid.…”

“…Many studies have emphasized the importance of MAPKs in the development and progression of endometriosis 55–57 . Additionally, both in vitro and in vivo investigations have shown that activation of the MEK5/ERK5 pathway is involved in oxidative stress‐elicited effects 40,58–60 . We here reported for the first time that S1P induces ERK5 activation in endometrial cells and that both pharmacological and genetic inhibition of ERK5 reverted the S1P‐dependent ROS production and proinflammatory cytokine expression.…”

“…[55][56][57] Additionally, both in vitro and in vivo investigations have shown that activation of the MEK5/ ERK5 pathway is involved in oxidative stress-elicited effects. 40,[58][59][60] We here reported for the first time that S1P induces ERK5 activation in endometrial cells and that both pharmacological and genetic inhibition of ERK5 reverted the S1P-dependent ROS production and proinflammatory cytokine expression. Very little literature evidence is available on the ability of S1P to activate ERK5.…”

“…We then examined whether, in HESC, S1P was capable of activating ERK5, a pivotal MAPK involved in ROS modulation, 40 expressed in endometrial tissues and endometriotic lesions as determined by qPCR (Figure 3A). To this end, HESC were treated with 100 nM S1P for different time intervals (from 5 to 60 min) before being lysed and subjected to Western blot analysis.…”