Abstract
Remote limb ischemic postconditioning (RLIP) is an experimental strategy in which short femoral artery ischemia reduces brain damage induced by a previous harmful ischemic insult. Ionic homeostasis maintenance in the CNS seems to play a relevant role in mediating RLIP neuroprotection and among the effectors, the sodium-calcium exchanger 1 (NCX1) may give an important contribution, being expressed in all CNS cells involved in brain ischemic pathophysiology. The aim of this work was to investigate whether the metal responsive transcription factor 1 (MTF-1), an important hypoxia sensitive transcription factor, may (i) interact and regulate NCX1, and (ii) play a role in the neuroprotective effect mediated by RLIP through NCX1 activation. Here we demonstrated that in brain ischemia induced by transient middle cerebral occlusion (tMCAO), MTF-1 is triggered by a subsequent temporary femoral artery occlusion (FAO) and represents a mediator of endogenous neuroprotection. More importantly, we showed that MTF-1 translocates to the nucleus where it binds the metal responsive element (MRE) located at −23/−17 bp of Ncx1 brain promoter thus activating its transcription and inducing an upregulation of NCX1 that has been demonstrated to be neuroprotective. Furthermore, RLIP restored MTF-1 and NCX1 protein levels in the ischemic rat brain cortex and the silencing of MTF-1 prevented the increase of NCX1 observed in RLIP protected rats, thus demonstrating a direct regulation of NCX1 by MTF-1 in the ischemic cortex of rat exposed to tMCAO followed by FAO. Moreover, silencing of MTF-1 significantly reduced the neuroprotective effect elicited by RLIP as demonstrated by the enlargement of brain infarct volume observed in rats subjected to RLIP and treated with MTF-1 silencing. Overall, MTF-dependent activation of NCX1 and their upregulation elicited by RLIP, besides unraveling a new molecular pathway of neuroprotection during brain ischemia, might represent an additional mechanism to intervene in stroke pathophysiology.
Highlights
In the last decade, remote limb ischemic postconditioning (RLIP) emerged as a potent neuroprotective strategy
We intended to exclude that the cobalt-induced activation of MRE1 and MRE2 sites by metal responsive transcription factor 1 (MTF-1) was dependent from HRE1 and HRE2 activation by hypoxia-inducible factor-1 (HIF-1), as previously reported[9]
In the present paper, we demonstrated, for the first time, that[1]: isoform 1 of the sodium–calcium exchanger is a new target of the transcriptional factor MTF-12; the plasma membrane sodium/calcium exchanger 1 may take part in the stroke neuroprotection elicited by remote limb postconditioning; and[3] MTF-1 mediates NCX1 upregulation occurring in the remote post-conditioned brain, taking part to stroke neuroprotection
Summary
Remote limb ischemic postconditioning (RLIP) emerged as a potent neuroprotective strategy. Valsecchi et al Cell Death and Disease (2021)12:423. Ca2+ and the entrance of Na+ ions or in the reverse mode. Considering that in the ischemic core a dramatic reduction of ATP occurs, it is conceivable to hypothesize that the absence of ATP impairs all ATP-dependent transporters, i.e., Na+/K+ATPase, forcing NCX to work in the reverse mode. The situation should be different in the penumbra region where ATP is still present. For these peculiar functions, NCX1 may counteract the ionic homeostasis dysregulation, that occurs during an ischemic insult, extruding Na+ ions from the cell and promoting Ca2+ refilling of the ER5, preserving the intracellular Ca2+ and Na+ concentrations within physiological levels in the brain[6]. Brain damage worsens in ischemic animals in which NCX1 is knocked out by antisense oligodeoxynucleotides[7] or in which NCX1 was genetically ablated and ameliorates when NCX1 is overexpressed[7]
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