Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Abstract

Objective Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injury. Methods Rat pups underwent common carotid artery ligation followed by either 150 min (severe model) or 100 min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) were used to examine their roles on BBB permeability. Results Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. Conclusions rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α’s effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.

Sestrin2 prevents age‐related intolerance to ischemia and reperfusion injury by modulating substrate metabolism

“…Moreover, Sesn2 is also induced in response to hypoxia; simulated ischemic conditions, such as hypoxia/glucose deprivation; and cerebral ischemia (27, 28, 62). Studies suggest that Sesn2 is a target of HIF‐1α, which is rapidly activated during myocardial ischemia (12), as experiments conducted in HIF‐1α–depleted cells demonstrate an absence of, or diminished, Sesn2 expression (27, 28, 63).…”

Recent Insights into the Biological Functions of Sestrins in Health and Disease

“…In rats subjects to severe hypoxic-ischemic (carotid artery ligation for 150 min), researchers found that the expression of Sesn2 and the infarct area were higher than that in sham rats and moderate hypoxic-ischemic group (carotid artery ligation for 100 min) [56]. Recombinant human Sesn2 attenuated brain infarct and edema, while silencing Sesn2 reversed these protective effects after severe hypoxic-ischemic.…”

“…Recombinant human Sesn2 attenuated brain infarct and edema, while silencing Sesn2 reversed these protective effects after severe hypoxic-ischemic. Mechanically, Sesn2 protected against severe hypoxic-ischemic encephalopathy through attenuating the blood-brain barrier permeability via inhibiting the expression vascular endothelial growth factor and promoting the expression of junction proteins [56]. In addition, the studies from the same group revealed that Sesn2 improved the infarct volume and neurological function through activating the AMPK pathway which in turn inhibits mTOR signaling and attenuates neuron apoptosis in rat hypoxic-ischemic encephalopathy model [57].…”

Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

“…Nrf2 is a redox‐sensitive transcription factor that translocates to the nucleus upon oxidative stress and binds to antioxidant reaction element (ARE) within the promoter of Nrf2 target genes, such as heme oxygenase‐1 (HO‐1), to initiate gene transcription . Intriguingly, numerous studies revealed that Sestrin2 participates in the progression of cerebral ischaemia/reperfusion injury and exerts neuroprotective functions against neuronal apoptosis and oxidative stress . Therefore, Sestrin2 is a promising target for neuroprotection.…”