Abstract
Ischemic stroke is characterized by insufficient blood supply to brain tissue and is associated with increased morbidity and mortality in adults worldwide. Growth arrest-specific protein 6 (GAS6) is a vitamin K-dependent protein and is widely expressed in the central nervous system. The biological functions of GAS6 are mediated by the interaction with TAM (Tyro3, Axl and Mertk) receptors, including cell survival and proliferation, immune regulation and apoptosis. Omentin-1, also known as intelectin-1 (ITLN-1), is a novel adipocytokine that is involved in a variety of biological events, such as insulin resistance, endothelial dysfunction, programmed cell death and metabolic disorders. Our previous study has found that omentin-1 act as a novel regulator of vascular and anti-apoptotic response in cerebral ischemia. However, the specific molecular mechanism of omentin-1’s protective effect on cerebral ischemia-reperfusion injury (IRI) is still unclear. First, the toxicity of recombinant human omentin-1 (rh-omentin) was assessed and a safe concentration was chosen for the next experiments. Then, rh-omentin exerted neuroprotection against hypoxia/reoxygenation (H/R) injury in N2a cells, indicated by increased cell viability, decreased LDH, ROS generation, and cell apoptotic rate. Furthermore, the similar protective effect was observed in omentin-1 overexpression cells constructed by lentivirus transfection. Rh-omentin could also inhibit H/R-induced apoptotic molecules, oxidative stress molecules, and GAS6/Axl signaling molecules which as evidence by increased omentin-1, GAS6, Axl, p-Axl, NQO1, HO-1, Nrf2, Bcl2 and decreased Bax expressions. However, GAS6 siRNA could reverse rh-omentin-induced neuroprotection and the levels of these molecules mentioned above. In conclusion, these findings suggest that omentin-1 treatment exerts neuroprotection against H/R injury partly via activating GAS6/Axl signaling at least. Therefore, these finding may favor omentin-1 a potential neuroprotective drug candidate to alleviate ischemia-reperfusion injury in clinic.
Highlights
Ischemic stroke is characterized by insufficient blood supply to brain tissue and is associated with increased morbidity and mortality in adults worldwide (Mendelson and Prabhakaran, 2021)
At mRNA level, omentin-1 and Growth arrestspecific protein 6 (GAS6) were down-regulated in H/R treated N2a cells
Pretreatment with rh-omentin could significantly increase omentin-1, GAS6, Axl, p-Axl, NQO1, HO-1, Nrf2, Bcl2 expressions and decrease Bax expression. These results suggested that rh-omentin might be able to improve oxidative stress and apoptosis, and activate GAS6/Axl signaling pathways in N2a cells injured by H/R (Figures 5A,B, vs. the control group, p < 0.05)
Summary
Ischemic stroke is characterized by insufficient blood supply to brain tissue and is associated with increased morbidity and mortality in adults worldwide (Mendelson and Prabhakaran, 2021). Vascular reconstruction is the standard treatment for cerebral ischemia, which is essential to alleviate ischemia injury and restore brain function. Reperfusion treatment induces additional damage to ischemic tissue, defined as cerebral ischemia-reperfusion injury (IRI) in clinic (Spescha et al, 2015). Understanding the molecular feature of cerebral IRI and alleviating IR mediated neuronal damage can increase the therapeutic efficiency of IR treatment. Maruyama et al confirmed that omentin-1 can promote endothelial cell function and angiogenesis in response to ischemia and inhibit apoptosis in rats with unilateral hind limb surgery (Maruyama et al, 2012). Our previous study has found that omentin-1 act as a novel regulator of vascular and anti-apoptotic response in cerebral ischemia (Gu et al, 2017). The specific molecular mechanism of omentin-1’s protective effect on cerebral IRI is still unclear
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