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.

Keywords: ERK5; KLF2/4; MEF2; RNS; ROS; antioxidant response; oxidative damage; oxidative stress.

Figure 1

Overview of the mechanisms of activation and downstream effectors of the MEK5/ERK5 pathway in response to oxidative stress. The rising in oxidative stress triggers MEK5/ERK5 activation, which, in turn, promotes an antioxidant response. (1) Laminar shear stress (LSS) induces mtROS production, which, in turn, leads to activation of the MEK5/ERK5/KLF2 pathway [72]. (2) H₂O₂ stimulation may activate the ERK5 pathway via SRC [36,57,58,62], MEKK2/3 [63] or MEK5 [75,76] activation. Continuous arrows indicate direct activation mechanisms and dashed arrows indicate demonstrated, but not direct, mechanisms. eNOS, endothelial nitric oxide synthase; NQO1, NAD(P)H quinone dehydrogenase 1; HO-1, heme oxygenase-1; TXN-1, thioredoxin-1; GPx-1, glutathione peroxidase (created using Biorender.com accessed on 23 March 2023).