Targeting mitochondrial NOX4/ROS to prevent hyperglycemia-induced hemorrhagic transformation after mechanical thrombectomy in acute ischemic stroke

This study examines whether mitochondrial NOX4 (mtNOX4) plays a crucial role in hemorrhagic transformation (HT) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS). The rat hyperglycemia-induced HT model and brain microvascular endothelial cells OGD/R model were used to simulate the process of HT after MT in human AIS. NOX4 siRNA induced NOX4 knockdown in vitro or NOX4 shRNA in vivo . MtNOX4/ROS was measured in vivo and in vitro . In vitro , tight junction (TJ) proteins and adhering junction (AJ) proteins were detected in endothelial cells. Infarct volume, HT, BBB damage, and neurological score were determined 24 h after cerebral ischemia in vivo . The induction of mitochondrial oxidative stress by mtNOX4/ROS disrupted AJ and TJ proteins after OGD/R. Furthermore, compared to the OGD/R group, NOX4 siRNA decreased the expression of mtNOX4/ROS and mitigated the downregulation of ZO-1, Occludin, Claudin-5, and VE-Cadherin. In vivo experiments demonstrated that NOX4 knockdown suppressed mtNOX4/ROS upregulation in the penumbra area compared to the HT group. Additionally, NOX4 knockdown reduced infarct volume and HT while improving BBB integrity and neurological outcomes. Targeting the mtNOX4/ROS pathway may be a potential treatment strategy to improve outcomes in patients suffering from HT after MT for AIS.