Role of ALK5/SMAD2/3 signaling in the regulation of NOX expression in cerebral ischemia/reperfusion injury.

Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) serve an important role in cerebral ischemia/reperfusion (I/R) injury. However, the mechanism by which ROS generation is regulated has not yet been fully elucidated. The present study aimed to explore the role of transforming growth factor-β signaling in ROS generation. Sprague Dawley rats were subjected to I/R injury and PC-12 cells were transfected with small interfering RNA against activin receptor-like kinase (ALK)5 or hypoxia/reoxygenation (H/R). The results indicated that I/R or H/R significantly increased ALK5 expression, SMAD2/3 phosphorylation and NOX2/4 expression and activity, concomitant with ROS generation and apoptosis. In addition, ALK5 knockdown significantly reversed changes induced by H/R treatment in PC-12 cells. These results suggest that ALK5/SMAD2/3 signaling serves a key role in oxidative stress. To the best of our knowledge, this is the first study to demonstrate that ALK5/SMAD2/3 activation is associated with the regulation of NOX2/4 expression and exacerbates I/R injury.