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CircUCK2 regulates HECTD1-mediated endothelial-mesenchymal transition inhibition by interacting with FUS and protects
Jun-Hong Zhuang1, Huan-Xiong Chen2, Ning Gao2
1Department of Neurology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, China.
Insights
Circular RNA UCK2 (circUCK2) protects against ischemic stroke (IS) by upregulating HECTD1 expression via FUS interaction, inhibiting endothelial-mesenchymal transition and blood-brain barrier damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- Ischemic stroke (IS) is a significant cerebrovascular disease with considerable impact.
- Current understanding of circUCK2's regulatory mechanisms in IS remains incomplete.
- circUCK2 has shown potential in alleviating neuronal damage in IS models.
Purpose of the Study:
- To elucidate the specific regulatory mechanisms of circUCK2 in ischemic stroke.
- To investigate the relationship between circUCK2, HECTD1, and endothelial-mesenchymal transition (EndoMT).
- To assess the protective effects of circUCK2 and HECTD1 on the blood-brain barrier (BBB) in IS.
Main Methods:
- Investigated circUCK2 and HECTD1 expression levels in IS models (in vitro and in vivo).
- Examined the effects of circUCK2 and HECTD1 overexpression on EndoMT and BBB integrity.
- Analyzed the interaction between circUCK2, HECTD1, and FUS (fused in sarcoma).
- Utilized transient middle cerebral artery occlusion (tMCAO) mouse models.
Main Results:
- Both circUCK2 and HECTD1 were found to be downregulated in IS models.
- Overexpression of circUCK2 or HECTD1 inhibited EndoMT and protected the BBB from damage in tMCAO mice.
- circUCK2 was shown to regulate HECTD1 expression through interaction with FUS.
- FUS overexpression partially reversed circUCK2's effect on EndoMT, and HECTD1 overexpression weakened FUS's effect.
Conclusions:
- circUCK2 upregulates HECTD1 expression by binding with FUS.
- This interaction inhibits EndoMT and alleviates BBB damage in ischemic stroke.
- circUCK2 serves as a potential therapeutic target for ischemic stroke treatment.
Abstract:
Ischemic stroke (IS) has become a cerebrovascular disease of widespread concern. Overexpression of circUCK2 alleviates neuronal damage in IS. However, the specific regulatory mechanisms of circUCK2 are not fully understood. In this study, we found that circUCK2 and HECT domain E3 ubiquitin ligase 1 (HECTD1) were downregulated in IS models in vitro and in vivo. Overexpression of circUCK2 or HECTD1 inhibited endothelial-mesenchymal transition (EndoMT) and protected the blood-brain barrier (BBB) in transient middle cerebral artery occlusion mice from damage. It was further discovered that circUCK2 regulated HECTD1 expressions by interacting with fused in sarcoma (FUS). Moreover, FUS overexpression partially restored the effect of circUCK2 on EndoMT, and overexpression of HECTD1 weakened the effect of FUS on EndoMT. Collectively, circUCK2 upregulates the expression of HECTD1 by combining with FUS and inhibits EndoMT to alleviate BBB damage in IS both in vivo and in vitro.
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