Abstract
The present study aimed to explore specific mechanisms involved in mediating the neuroprotective effects of Smad ubiquitination regulatory factor 2 (Smurf2) in cerebral ischemic injury. A middle cerebral artery occlusion (MCAO) mouse model and an oxygen–glucose deprivation (OGD)–treated neuron model were developed. The expression of Smurf2, Yin Yang 1 (YY1), hypoxia-inducible factor-1 alpha (HIF1α), and DNA damage–inducible transcript 4 gene (DDIT4) was analyzed. Thereafter, the expression of Smurf2, YY1, HIF1α, and DDIT4 was altered in the MCAO mice and OGD-treated neurons. Apoptosis in tissues and cerebral infarction were assessed. In neurons, the expression of apoptosis-related proteins, viability, and apoptosis were assessed, followed by evaluation of lactate dehydrogenase leakage rate. The interaction between Smurf2 and YY1 was analyzed by coimmunoprecipitation assay and that between YY1 ubiquitination by in vivo ubiquitination experiment. The results showed downregulation of Smurf2 and upregulation of YY1, HIF1α, and DDIT4 in both MCAO mice and OGD-treated neurons. Smurf2 elevated YY1 ubiquitination and degradation, and YY1 increased HIF1α expression to promote DDIT4 in neurons. Overexpressed Smurf2 or downregulated YY1, HIF1α, or DDIT4 reduced the volume of cerebral infarction and apoptosis in MCAO mice, while enhancing cell viability and reducing apoptosis and lactate dehydrogenase leakage in OGD-treated neurons. In summary, our findings elucidated a neuroprotective role of Smurf2 in cerebral ischemic injury via inactivation of the YY1/HIF1α/DDIT4 axis.
Highlights
Addressing cerebral ischemic injury, but the majority of current neuroprotective agents are limited by poor efficacy or significant toxicity/side effects (4)
damage–inducible transcript 4 gene (DDIT4) was found to promote cardiomyocyte apoptosis and lead to ischemia-reperfusion injury (15). Considering these findings together, it was hypothesized that the Smad ubiquitination regulatory factor 2 (Smurf2)/Yin Yang 1 (YY1)/ hypoxia-inducible factor-1 alpha (HIF1α)/DDIT4 axis modulates the development of cerebral ischemic injury, and the current study was designed to investigate this hypothesis using middle cerebral artery occlusion (MCAO) mouse models and oxygen–glucose deprivation (OGD)-treated neuron models
The ischemic penumbra tissues of mice in each group were selected for H&E staining, the results of which displayed no significant differences between the morphological structure of brain tissues of sham-operated mice and normal mice, and showed that gliocyte hypertrophy and proliferation, cell and interstitial edema, and neuronal necrosis were observed in MCAO rats (Fig. 1D)
Summary
Addressing cerebral ischemic injury, but the majority of current neuroprotective agents are limited by poor efficacy or significant toxicity/side effects (4). YY1 serves as a dual function transcription factor, which can regulate transcriptional activation and repression of multiple genes related to various cellular processes, like cell differentiation, survival, apoptosis, autophagy, division, and DNA repair (10). It has been established in an earlier study that YY1 can induce neuronal glycolysis to trigger cerebral ischemia/ reperfusion injury in vivo (11). DDIT4 was found to promote cardiomyocyte apoptosis and lead to ischemia-reperfusion injury (15) Considering these findings together, it was hypothesized that the Smurf2/YY1/ HIF1α/DDIT4 axis modulates the development of cerebral ischemic injury, and the current study was designed to investigate this hypothesis using MCAO mouse models and OGD-treated neuron models
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