SMP30 alleviates cerebral ischemia/reperfusion-induced neuronal injury by inhibiting HDAC4/PSD-95 to preserve mitochondrial function.

Abstract

Ischemic stroke is a major cause of global death and permanent disability. Major consequences of ischemic stroke include neuronal mitochondrial dysfunction. We investigated the effects of senescence marker protein 30 (SMP30) on mitochondria-mediated apoptosis and histone deacetylase 4 (HDAC4)/postsynaptic density-95 (PSD-95) signaling in stroke models in vivo and in vitro. Rats with middle cerebral artery occlusion/reperfusion (MCAO/R) were used to simulate cerebral ischemia/reperfusion (I/R) injury. SMP30 was downregulated in the brain tissues of rats after I/R induction. SMP30 overexpression decreased MCAO/R-induced infarct volumes and improved neurologic function and histopathological changes. Increasing SMP30 expression suppressed neuronal apoptosis and reduced mitochondrial dysfunction. SMP30 overexpression in SH-SY5Y and PC12 cells treated with oxygen-glucose deprivation/reoxygenation (OGD/R) decreased HDAC4 and PSD-95 expression; PSD-95 could bind to HDAC4. Furthermore, HDAC4 upregulation abolished the effects of SMP30 overexpression on OGD/R-induced apoptosis and mitochondrial dysfunction in SH-SY5Y cells. Together, these findings indicate that SMP30 alleviates cerebral I/R-induced neuronal injury by inhibiting HDAC4/PSD-95 to preserve mitochondrial function. These interactions might provide new treatment methods for patients with ischemic stroke.