Introduction: Cerebral ischemia and reperfusion (I/R) injury occurs after endovascular mechanical thrombectomy for patients with acute ischemic stroke. MicroRNA-29a (miR-29a) is involved in regulating cerebral ischemia process, but its underlying mechanism is unclear. This study investigated the role of miR-29a in cerebral I/R injury after mechanical reperfusion in transient middle cerebral artery occlusion (tMCAO) animal model.
Methods: The intraluminal filament tMCAO model was established in male rats with 2 hour ischemia followed by reperfusion. The expression of miR-29a in the infarction core and peri-infarct cortex and whole blood were quantified at 0, 3, 12, and 24 hour after reperfusion. Permanent MCAO model was also evaluated at 2-hour and 24-hour ischemia. Intravenous miR-29a-5p agomir was delivered immediately after reperfusion or before reperfusion. Infarct volume, brain water content, neurological score and blood-brain barrier damage, and the expression of miR-29a-5p, NADPH oxidase (NOX4), aquaporin-4 and caspase-3 were determined at 24-hour after ischemia.
Results: MiR-29a-5p levels in the infarction core and peri-infarct cortex were significantly decreased at 3 hours after reperfusion in tMCAO group. The decreased levels of miR-29a-5p in brain tissue and whole blood lasted for 24 hours after ischemia. Intravenous miR-29a-5p agomir reduced infarct volume (p<0.01) at 24-hour after ischemia compared to the tMCAO group. MiR-29a-5p agomir attenuated brain edema and reduced reperfusion-induced blood-brain barrier breakdown, resulting in improved neurological outcome (p<0.05). Intravenous miR-29a-5p agomir increased the expression of miR-29a-5p and suppressed the up-regulation of NOX4, AQP4, caspase-3 in both the infarction core and peri-infarct cortex compared with the tMCAO group (p<0.05). Dual-luciferase reporter system showed that NOX4 was the direct target gene of miR-29a-5p.
Conclusions: MiR-29a-5p overexpression protects against cerebral I/R injury via downregulating NOX 4. Infusion of miR-29a-5p agomir immediately after reperfusion and before reperfusion represents a novel adjunctive therapeutic strategy to improve outcome after mechanical reperfusion for acute stroke.
Patient Care: Our translational research suggest that intravenous infusion of miR-29a-5p agomir immediately after reperfusion and before reperfusion may represent a novel adjunctive therapeutic strategy to improve outcome after endovascular mechanical reperfusion for acute ischemic stroke.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the role of miR-29a-5p in cerebral ischemia and reperfusion injury after mechanical reperfusion in transient middle cerebral artery occlusion animal model. 2) Discuss the mechanism of miR-29a-5p as a potential neuroprotective target. 3) Identify an effective treatment by intravenous infusion of miR-29a-5p agomir immediately after reperfusion and before reperfusion to improve outcome after mechanical reperfusion for acute stroke in rat models.