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.