Enhancing S-nitrosoglutathione reductase decreases S-nitrosylation of Drp1 and reduces neuronal apoptosis in experimental subarachnoid hemorrhage both in vivo and in vitro

Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke with a high mortality and disability rate. Nitric oxide (NO) can promote blood supply through vasodilation, leading to protein S-nitrosylation. However, the function of S-nitrosylation in neurons after SAH remains unclear. Excessive NO in the pathological state is converted into S-nitrosoglutathione (GSNO) and stored in cells, which leads to high S-nitrosylation of intracellular proteins and causes nitrosative stress. S-nitrosoglutathione reductase (GSNOR) promotes GSNO degradation and protects cells from excessive S-nitrosylation. We conducted an in vivo rat carotid puncture model and an in vitro neuron hemoglobin intervention. The results showed that SAH induction increased NO, GSNO, neuron protein S-nitrosylation, and neuronal apoptosis, while decreasing the level and activity of GSNOR. GSNOR overexpression by lentivirus decreased GSNO but had little effect on NO. GSNOR overexpression also improved short-and long-term neurobehavioral outcomes in rats and alleviated nitrosative stress. Furthermore, GSNOR reduced neuronal apoptosis and played a neuroprotective role by alleviating Drp1 S-nitrosylation, reducing mitochondrial division. Thus, the regulation of GSNOR in early brain injury and neuronal denitrosylation may play an important role in neuroprotection.

Automated summary

Subarachnoid hemorrhage (SAH) is a highly fatal and disabling hemorrhagic stroke. Nitric oxide (NO) can promote blood supply by vasodilation, but its role in neurons after SAH is not clear. Excessive NO can be converted into S-nitrosoglutathione (GSNO) and stored in cells, causing nitrosative stress. S-nitrosoglutathione reductase (GSNOR) promotes GSNO degradation and protects cells. This study found that overexpression of GSNOR can reduce GSNO levels, improve neurobehavioral outcomes, and alleviate nitrosative stress. Furthermore, GSNOR plays a neuroprotective role by reducing mitochondrial division and neuronal apoptosis. Therefore, regulation of GSNOR may be important in early brain injury and neuroprotection.