circCELF1 Induces the Apoptosis and Autophagy of Astrocytes in Ischemic Stroke via Upregulating NFAT5

Abstract

<b><i>Introduction:</i></b> Ischemic stroke, an abrupt blockage of artery, accounting for the most cases of stroke, causes high neurological mortality across the world. Recent evidence has uncovered that circular RNAs (circRNAs) highly engage in ischemic stroke-related neuronal injury. This study concentrated on a novel circRNA hsa_circ_0000304 (termed as circCELF1), trying to unveil its role and underlying mechanism in ischemic stroke. <b><i>Methods:</i></b> RT-qPCR and Western blot assays were conducted to detect the expression levels of RNA and protein, respectively. Functional analysis was performed to evaluate the influences of circCELF1 expression on astrocyte apoptosis and autophagy. Multiple mechanism assays were performed to probe the molecular mechanism underlying circCELF1 regulation. The oxygen-glucose deprivation/reoxygenation (OGD/R)-induced astrocytes model and transient middle cerebral artery occlusion (tMCAO) mouse model were constructed. <b><i>Results:</i></b> circCELF1 was found to be upregulated in OGD/R-induced astrocytes, relative to normal astrocytes. circCELF1 knockdown repressed the apoptosis and autophagy of astrocytes. The in vivo study conducted with the tMCAO model also revealed that circCELF1 or NFAT5 deficiency contributed to the suppression of neural injury. Further, circCELF1 was uncovered to elevate NFAT5 expression via recruiting DDX54, functionally promoting astrocyte apoptosis and autophagy. <b><i>Conclusion:</i></b> circCELF1 recruits DDX54 to upregulate NFAT5, by which astrocyte apoptosis and autophagy are stimulated.

Plasma levels of neuron/glia-derived apoptotic bodies, an in vivo biomarker of apoptosis, predicts infarct growth and functional outcome in patients with ischemic stroke

“…Over the last two decades, several histological and molecular studies in vitro and in vivo using animal models of cerebral ischemia have shown that apoptosis is the main mechanism of neuronal damage in the penumbra [11][12][13][14][15][16][17][18][19][20][21][22][23][24], although other types of regulated cell death, such as autophagy, necroptosis, ferroptosis, parthanatosis, phagoptosis and pyroptosis, may occur during the ischemic event [16, [25][26][27][28][29]. However, there have been few studies on cerebral apoptosis in patients with ischemic stroke because of limitations in the methods for the detection of this death mechanism, which require tissue samples from patients to be taken invasively or uorescent or radiolabeled probes to be injected throughout the body .…”