Neuroprotective action of PHD inhibitors is predominantly HIF‐1‐independentстатья
Статья опубликована в высокорейтинговом журнале
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Дата последнего поиска статьи во внешних источниках: 27 ноября 2019 г.
Аннотация:Hypoxia-inducible factor (HIF-1) as the primary factor mediating
gene-dependent cellular responses to hypoxia represents
an attractive target for the therapeutic interventions. The
current Editorial comments on an as yet underestimated facet
of HIF-1–related research. The activity of HIF-1 is being
regulated by the availability of its a-subunit HIF-1a, which
undergoes quick degradation. The process of degradation is
initiated by prolyl 4-hydroxylase (PHD). PHD is an oxygendependent
enzyme and therefore is inactivated in hypoxia, in
turn resulting in HIF-1a stabilization, its dimerization with HIF-
1b subunit thereby producing the transcriptionally active factor.
It has been suggested that pharmacological inhibition of PHD
activity might give the same results. Indeed, a large body of
evidence on beneficial effects of PHD inhibitors has been
accumulated in multiple laboratory and clinical trials. In
addition to them, a paper by Li and colleagues published in
this issue of Journal of Neurochemistry also reports that
inhibition of PHD by adaptaquin reduces hypoxic-ischemic
brain injury in a neonatal mouse model. When dissecting the
underlying molecular mechanisms, Li and colleagues surprisingly
found that the observed effects appear to be independent
of HIF-1. These findings draw attention back to the question
about possible HIF-1 effects independent of PHD inhibitors,
which has been raised several years ago but has not received
sufficient attention so far, and is being discussed in this
Editorial. One of the possible mechanisms might be ascribed
to the ferroptosis pathway affected by PHD inhibitors but this
question needs further careful studies, as well as clarification
of other mechanisms possibly involved. Even if they represent
a prospective therapeutic strategy, the lack of current knowledge
about endogenous targets of PHD inhibitors, except for
PHD, calls for a careful and balanced approach toward their
clinical use.