Cerebral ischemia‐reperfusion is modulated by macrophage‐stimulating 1 through the MAPK‐ERK signaling pathway

Abstract

Cerebral ischemia-reperfusion (IR) injury is associated with mitochondrial damage. Macrophage-stimulating 1 (MST1) reportedly stimulates mitochondrial apoptosis by suppressing BCL-2. We investigated whether MST1 promotes the progression of cerebral IR injury by inducing mitochondrial dysfunction in vivo and in vitro. Western blot analysis, quantitative polymerase chain reaction, immunofluorescence, and mitochondrial function assays were conducted in cells from wild-type and Mst1-knockout mice subjected to cerebral IR injury. MST1 expression in wild-type glial cells increased following cerebral IR injury. Cerebral IR injury reduced the mitochondrial membrane potential and mitochondrial metabolism in glial cells, while it enhanced mitochondrial reactive oxygen species generation and mitochondrial calcium levels in these cells. The deletion of Mst1 attenuated cerebral IR injury by improving mitochondrial function and reducing mitochondrial damage. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was suppressed in wild-type glial cell upon cerebral IR injury but was reactivated in Mst1-knockout glial cell. Accordingly, blocking the MAPK/ERK pathway abolished the beneficial effects of Mst1 deletion during cerebral IR injury by inducing mitochondrial damage in glial cells. Our results suggest that cerebral IR injury is associated with MST1 upregulation in the brain, while the genetic ablation of Mst1 can attenuate mitochondrial damage and sustain brain function following cerebral IR injury.

Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

“…The Wnt signaling pathways exhibit crosstalk with a various key signaling pathways, forming a network that play a broad role in the regulation of I/R injury. Besides the mentioned crosstalk signaling pathways, we hypothesize that other signaling pathways may also be involved in this mechanism, among them, the Rho/Rho-associated protein kinase, 503 , 504 MAPK/ERK, 505 JAK/STAT, 468 , 506 Nrf2, 507 and AMPK 508 signaling pathways deserve further investigation.…”

Functional material-mediated wireless physical stimulation for neuro-modulation and regeneration

“…63 ERK pathway activation is associated with the upregulation of anti-apoptotic genes, which may explain the pro-survival effect of ERK in glial cells. 64 Activated MAPK can either translocate to the nucleus and regulate the activity of transcription factors such as the transcription factor Elk1, whose phosphorylation is necessary for the activation of c-Fos, a marker of neuronal activity, 65 or simply stay in the cytoplasm where it regulates other subcellular functions through substrates such as the ribosomal S6 kinase (RSK) protein kinase family. 66 On the basis of its regulation of neural cells, ES has been used as a powerful tool for neurological disease and injury therapies.…”

Study on the Mechanism of Üstikuddus Sherbiti in Ischemic Cerebrovascular Diseases: Based on Network Pharmacology

“…Plasma levels of AnxA1 are reduced in stroke, and AnxA1 can act on human platelets, thereby inhibiting the classic thrombin-induced internal-outside signaling events; for example, Akt activation, intracellular calcium release, and Ras-related protein 1 (Rap1) expression reduce αβ activation without changing its surface expression [58]. e MAPK signaling pathway is also one of the important therapeutic targets for ischemiareperfusion injury [59]. Mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK), the pathway is inhibited in wild-type glial cells after brain IR injury but is reactivated in glial cells where the Mst1 gene is knocked out.…”

“…Mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK), the pathway is inhibited in wild-type glial cells after brain IR injury but is reactivated in glial cells where the Mst1 gene is knocked out. erefore, blocking the MAPK/ERK pathway can induce mitochondrial damage eliminates the beneficial effects of macrophage stimulator 1 (MST1) loss during brain IR injury [59]. HIF-1 and erythropoietin can be regulated by PI3K/Akt in brain tissue and affect brain deficiency, antiinflammatory effect after blood reperfusion [60].…”