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.