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CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke
Yanfang Liu1,2, Yufeng Li1,2, Jiankun Zang1,2
1Department of Neurology and Stroke Center (Y. Liu, Y. Li, J.Z., T.Z., Y.L., Z.T., Y.Z., L.H., Y.W., X.S., Z.W., D.D., A.X., D.L.), The First Affiliated Hospital of Jinan University, Guangzhou, China.
Insights
Circular RNA derived from oxoglutarate dehydrogenase (CircOGDH) shows promise as a noninvasive biomarker for predicting the penumbra in acute ischemic stroke patients. Its levels correlate with penumbra size and may serve as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Biomarker Discovery
Background:
- Acute ischemic stroke (AIS) poses a significant global health challenge, leading to disability and mortality.
- Accurate prediction of the ischemic penumbra is critical for guiding reperfusion therapy decisions.
- A need exists for a fast, inexpensive, noninvasive, and clinically translatable biomarker for post-stroke penumbra assessment.
Purpose of the Study:
- To investigate circular RNA derived from oxoglutarate dehydrogenase (CircOGDH) as a potential biomarker for penumbra in AIS patients.
- To explore the role of CircOGDH in ischemic neuronal damage.
- To assess the diagnostic and therapeutic potential of CircOGDH in AIS.
Main Methods:
- CircOGDH expression was quantified in mouse models and human AIS patient plasma using quantitative polymerase chain reaction.
- Penumbra volumes were assessed using magnetic resonance imaging.
- Interactions between CircOGDH, miR-5112, and COL4A4 were investigated using molecular biology techniques, including FISH, RIP, and luciferase assays.
- Exosome isolation and characterization were performed using electron microscopy and nanoparticle tracking analysis.
Main Results:
- CircOGDH expression was significantly upregulated in the penumbra of AIS mouse models and in the plasma of AIS patients (54-fold increase).
- CircOGDH levels positively correlated with penumbra size in AIS patients.
- CircOGDH sequesters miR-5112, enhancing COL4A4 expression and promoting neuronal damage; knockdown of CircOGDH improved neuronal viability.
- CircOGDH was highly expressed in plasma exosomes of AIS patients, correlating with brain tissue expression.
Conclusions:
- CircOGDH is a promising predictive biomarker for penumbra in AIS patients, detectable in peripheral blood exosomes.
- CircOGDH may serve as a therapeutic target for modulating ischemia-induced neuronal viability.
- The findings highlight CircOGDH's potential for clinical application in AIS management.
Background:
Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage.
Methods:
CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes.
Results:
CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals.
Conclusions:
These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.
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