CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke

Abstract

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 in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. ADV-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type VI, alpha VI) 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.

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

“…The ectopic expression of miR-124 in the cortex promotes the differentiation of neural progenitor cells into neuronal lines, and further improves the anti-ischemic ability through cortical neurogenesis ( Zhou and Qi, 2021 ). Recent studies have reported that CircOGDH (cyclic RNA derived from ketoglutarate dehydrogenase) is highly expressed in plasma exosomes of patients with IS, and CircOGDH interacts with miR-5112 in primary cortical neurons to increase neuronal damage ( Liu Y. et al, 2022 ). By contrast, knockdown of CircOGDH significantly enhanced neuronal viability under ischemic conditions.…”

“…By contrast, knockdown of CircOGDH significantly enhanced neuronal viability under ischemic conditions. Therefore, CircOGDH and miR-5112 may be potential therapeutic targets for regulating the viability of ischemic neurons ( Liu Y. et al, 2022 ).…”

A Novel Perspective on Ischemic Stroke: A Review of Exosome and Noncoding RNA Studies

“…In animal and human experiments, they observed significantly increased expression of exosomal CircOGDH in the ischemic mouse primary cortical neurons and plasma of AIS patients, as compared to normoxic condition and noncerebrovascular disease controls, and the level of CircOGDH in the blood was positively correlated with the size of the penumbra tissue. Mechanistically, ischemic neuron-derived exosomes transported CircOGDH from the penumbra tissue to peripheral blood, and then upregulated COL4A4 (Gallus collagen, type VI, alpha VI) expression with sequestering of miR-5112, resulting in neuronal apoptosis [ 25 ]. Their study provided a potential intervention wherein knocking down CircOGDH could enhance neuronal cell viability in the ischemic penumbra tissue, contributing to improving neurological deficits in the acute phase of ischemic stroke.…”

Integrated Analysis of Immune-Related circRNA-miRNA-mRNA Regulatory Network in Ischemic Stroke

“…In addition, exosomes can carry circRNA across the blood-brain barrier, allowing circRNA to exist stably in peripheral blood, making circRNA promising as a novel diagnostic and prognostic biomarker for IS ( 14 ). A recent study reported that CircOGDH expression was upregulated in the plasma of IS patients, and the CircOGDH expression was positively correlated with penumbra size ( 15 ). Li et al examined circulating blood circRNA expression profiles of acute stroke patients and healthy controls and identified differentially expressed circRNAs in IS patients ( 16 ).…”