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Ferroptosis of microvascular pericytes contributes to ischemia–reperfusion injury in mice
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DOI：10.1177/0271678x261463955.png)
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Abstract
En 中文
<jats:p>
Ferroptosis is an iron-dependent form of programmed cell death implicated in various pathological conditions. We investigated whether ferroptosis contributes to acute ischemic stroke using a transient middle cerebral artery occlusion model in pial collateral-deficient CB-17/Icr-+/+Jcl mice. Mice were subjected to 90 min of ischemia followed by reperfusion, and the effects of the ferroptosis inhibitor UAMC-3203 on infarct evolution and post-stroke histological changes were examined. UAMC-3203 increased the survival of CD13-positive pericytes within infarct areas and enhanced infarct reduction in the subacute phase. In vitro, the glutathione peroxidase 4 inhibitor RAS-selective lethal 3 (RSL3) induced dose-dependent cell death in pericytes but not in endothelial cells, which was suppressed by UAMC-3203 but not by inhibitors of apoptosis or necroptosis. RSL3 induced lipid peroxidation in pericytes, as evidenced by malondialdehyde accumulation. Extracellular ferrous iron (Fe
<jats:sup>2+</jats:sup>
), but not ferric iron (Fe
<jats:sup>3+</jats:sup>
) or transferrin, caused intracellular Fe
<jats:sup>2+</jats:sup>
accumulation and cell death in pericytes, which was further enhanced by oxygen–glucose deprivation with reperfusion and suppressed by UAMC-3203. Myelin debris containing abundant Fe
<jats:sup>2+</jats:sup>
induced ferroptosis in cultured pericytes. These findings indicate that pericytes are a major ferroptosis-vulnerable cell type during ischemia–reperfusion and may represent a therapeutic target in acute ischemic stroke.
</jats:p>
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