Identification of NMT1/MA/VPS15 signal pathway as potential therapeutic target in rat cerebral ischemia injury

Abstract

Fatty acids play a critical role in cerebral ischemia injury through the regulation of lipid metabolism and inflammatory signaling. Myristic acid (MA), a 14‑carbon saturated fatty acid, serves as a substrate of N-myristoyltransferase 1 (NMT1) and modulates protein function and subcellular localization via myristoylation. We show here that intraperitoneal injection of MA has no effect on the infarct volume after rat cerebral ischemia-reperfusion (I/R) injury. However, our results reveal that the level of MA within the penumbra of ischemic brain is increased and that ischemia-induced downregulation of NMT1 is responsible for the increase of MA. We further show that upregulation of MA by knockdown of NMT1 exacerbates cerebral ischemia injury, while downregulation of MA by BCtDCS (bilateral and cathodal transcranial direct current stimulation) protects against cerebral ischemia injury. Furthermore, we demonstrate that MA reduces the expression of VPS15 (phosphoinositide 3-kinase regulatory subunit 4) to exacerbate cerebral ischemia injury, and that NMT1 acts on MA to regulate VPS15 expression in the ischemic cerebral cortex. Together, this study provides the first evidence identifying NMT1/MA/VPS15 signal pathway as potential target for stroke therapy and suggests that BCtDCS may act on MA-dependent signal pathway to confer neuroprotection.