Impact of endogenous vasohibin 1 and vasohibin 2 gene expression on ferroptosis in a mouse cerebral infarction model

Abstract

The vasohibin 1 (Vash1) and vasohibin 2 (Vash2) genes, known for their role in regulating angiogenesis, are also implicated in various cellular processes, including ferroptosis, a form of programmed cell death. However, the relationship between the endogenous Vash1 and Vash2 gene and ferroptosis in ischemic stroke was unknown. In this study, we investigated the function of the endogenous vasohibin genes in ferroptosis in a transient middle cerebral artery occlusion mice model. Motor function, infarct volume, and the expression levels of ferroptosis inhibitor GPX4 and the ferroptosis marker ACSL4 were evaluated with three experimental groups including wild-type (n = 24), Vash1 (+/–) mice (n = 24), and Vash2 (+/–) mice (n = 24). The cerebral infarct volume of Vash2 (+/–) mice was significantly larger than in Vash1 (+/–) mice. Compared with the Vash1 (+/–) mice, the Vash2 (+/–) mice exhibited significantly worse motor recovery and larger infarct volumes 24 h after ischemia–reperfusion. Western blot revealed that these detrimental effects in Vash2 (+/–) mice were linked to the downregulated NRF2 and HIF1-α expression. It further demonstrated that the expression level of GPX4 was significantly lower, whereas ACSL4 expression level was significantly higher in the Vash2 (+/–) group compared with the Vash1 (+/–) group. These findings highlight the distinct roles of Vash1 and Vash2 in cerebral ischemia. The reduction of Vash1 exhibits neuroprotective while reducing the Vash2 expression exacerbates ischemic injury through distinct pathways. Targeting regulated Vash1 and Vash2 expressions may offer novel therapeutic strategies for mitigating reperfusion injury.

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