Title : miR30c-mimic ameliorates acute ischemic stroke in mice by reducing thromboinflammation and attenuating neuronal ER stress
Abstract:
Decreased expression of endogenous miR-30c has been linked to numerous pathological conditions in both patients and animal models, including various cancers, hyperlipidemia, atherosclerosis, hyperglycemia, and diabetes. Systemic administration of a miR-30c mimic has been demonstrated to reduce hyperlipidemia and atherosclerosis. Conversely, inhibition of hepatic miR-30c with anti-miR-30c increased hyperlipidemia and atherosclerosis in animal models. These findings suggest that miR-30c could be an attractive target for therapeutic interventions. However, its role in regulating cerebral ischemia/reperfusion injury remains poorly understood. This study explores the potential impact of miR-30c in reducing post-stroke thrombotic and inflammatory responses by inhibiting PAI-1 expression in brain endothelial cells and reducing neuronal cell ER stress, thus mitigating brain damage from stroke. To this end, adult old mice underwent 45 minutes of middle cerebral artery occlusion (MCAo) followed by reperfusion. miR-30c mimic was intravenously administered three hours post-ischemia. The results showed that systemic administration of the miR-30c mimic reduced infarct size and improved functional outcomes on day 3 after stroke in a dose-dependent manner (0.5 to 5 mg/kg). The neuroprotective effects were associated with: 1) decreased thrombosis and improved cerebral perfusion by reducing intravascular fibrin and platelet deposition through the inhibition of PAI-1 expression in brain microvascular endothelial cells, and 2) reduced stroke-induced ER stress, thereby preventing apoptosis. In summary, our results indicate that elevating miR-30c could be a novel strategy for protecting against cerebral ischemia/reperfusion injury by modulating neurovascular functions across multiple cell types in both blood and brain.
Keywords: miR30c, Thromboinflammation, ER Stress, Ischemic Stroke
