4.2. Possible mechanisms for the involvement of CYP and their metabolites in the pathophysiological processes of high-altitude disease
High-altitude hypoxia affects the physiological functions of the body. CYP is an important enzyme that metabolizes biologically active endogenous substances. The fact that CYP and their metabolites are regulated by hypoxia and are expressed in a wide range of hypoxic disorders suggests that CYP and their metabolites may be involved in the pathophysiology of high-altitude diseases. Combined with literature reports, we hypothesized that the involvement of CYP and their metabolites in the pathophysiological processes of high-altitude disease may be related to three mechanisms: regulation of vascular tone, angiogenesis, and inflammatory response (Figure 3).
Hypoxia induces vasodilation in peripheral circulation and vasoconstriction in pulmonary circulation, whereas vascular self-regulation under hypoxia provides cellular and organismal adaptation to hypoxia. EET and HETE are important modulators of vascular tone and are central to the regulation of vascular responses under hypoxia. In a plateau environment, hypoxia-induced pulmonary vasoconstriction is a response of the pulmonary vasculature to reduced oxygen availability and involves the inhibition of oxygen-sensitive K+ channels, leading to the depolarization of pulmonary artery smooth muscle cells and activation of voltage-gated Ca2+ channels. EET has a well-documented role as an endothelium-derived vasodilator in the systemic vasculature. Endothelial cells produce EET via the CYP2 family phospholipase-A2(PLA2), which is metabolized to DHETs, and EET and DHETs activate calcium-dependent K+(K+Ca) channels. However, in pulmonary circulation, they are produced by vascular smooth muscle cells and enhance vasoconstriction. The increased expression of EET under hypoxia explains the pathogenesis of HAPH to some extent. HETE is produced by CYP4A metabolism, and HETE reduces the open probability of K+Ca and inhibits Na-K-ATPase, leading to smooth muscle cell membrane depolarization and activation of L-type Ca2+ channels, which induces contraction. The expression of HETE is downregulated in the brain under hypoxia, which in turn explains to some extent the cerebral vasodilatation under hypoxia.
Angiogenesis is a typical response to hypoxia and the formation of new capillaries increases the transport of oxygen to hypoxic cells. There may be a link between angiogenesis under hypoxia and CYP (in particular, the CYP metabolites EET and HETE). We propose that EET and HETE promote angiogenesis under hypoxia for two main reasons: first, these metabolites promote the proliferation and migration of vascular endothelial cells, and second, they promote the tube-forming capacity of endothelial cells, which facilitates neovascularization (Capozzi et al., 2014; Michaelis et al., 2005). This may be related to the expression of VEGF. Hypoxia induces stimulation of angiogenesis through transcription of VEGF, and EET and HETE are closely related to the role of VEGF regulation. EET enhanced VEGF-induced angiogenesis. VEGF increases CYP2C promoter activity in endothelial cells and induces CYP2C8 expression, leading to increased intracellular EET levels. The EET receptor antagonist 14,15- EEZE inhibits VEGF-induced tube formation in endothelial cells under hypoxic conditions (Zhang et al., 2021; Zhao et al., 2018). This suggests that the pro-angiogenic activity of EET under hypoxia is mediated, at least in part, by VEGF. HETE also plays an important role in VEGF-dependent angiogenesis (Chen et al., 2016). In addition, angiogenesis under hypoxia may also be associated with CYP-mediated degradation of the extracellular matrix, which provides space for endothelial cell migration and promotes angiogenesis under hypoxia.
The inflammatory response is activated in hypoxic diseases when the body is hypoxic, aerobic oxidation is converted to glycolysis, which increases the level of adenosine in the body, and the adenosine A2A receptor (A2AR) is activated, which causes microglial cells to release a variety of inflammatory factors. The inflammatory response is involved in the pathogenesis and development of many hypoxic diseases, and endogenous metabolites of CYP, such as EET and HETE, regulate inflammation. The NF-κB pathway is one of the main mechanisms through which EETs exert anti-inflammatory effects. EETs can reduce levels of inflammatory mediators, such as TNF-α, IL-1α, and C-reactive protein by inhibiting the NF-κB pathway, thereby exerting anti-inflammatory effects. In addition, EETs reduced inflammatory responses by downregulating the activities of COX and LOX enzymes and their corresponding metabolites. However, HETE is a pro-inflammatory mediator that substantially stimulates the production of inflammatory cytokines/chemokines in endothelial cells, including IL-8, IL-13, IL-4, and prostaglandin E2, in addition to stimulating the activation of the NF-κB, STAT3, and MAPK/ERK pathways. The current study showed that increasing the levels of endogenous EETs or HETE by CYP overexpression or direct exogenous addition of EETs or HETE could have potent inhibitory or promoting effects on hypoxia-induced inflammatory responses. Therefore, we hypothesized that hypoxia regulates changes in CYP expression, which in turn leads to changes in EET and HETE expression, which in turn regulates inflammatory changes under hypoxia at the source and further suppresses homeostatic imbalances under hypoxia. However, EET and HETE have opposite roles in regulating inflammatory responses, and how hypoxia regulates their dynamic balance to regulate the physiological processes of various plateau diseases requires more in-depth research.