GATA3 modulation of mitochondrial oxidative stress inhibits cerebrovascular remodeling-mediated ischemic stroke by suppressing MBVSMC phenotypic transformation

Abstract

Ischemic stroke (IS) is the most predominant type of stroke, and cerebrovascular remodeling that occurs in response to risk factors facilitates its development. Mouse brain vascular smooth muscle cells (MBVSMCs) undergo phenotypic transformation during cerebrovascular remodeling, and reactive oxygen species (ROS) are a major driver of this process. The transcription factor of GATA binding protein 3 (GATA3) has been shown to enhance the neuroprotective effect induced by ischemic preconditioning. However, its involvement in cerebrovascular remodeling and the underlying mechanism are yet to be elucidated. Our findings showed that the expression of GATA3 was reduced in the cerebrovascular remodeling model constructed using angiotensin II (AngII)-induced MBVSMCs. In addition, the overexpression of GATA3 and the treatment of MBVSMCs with AngII revealed that the activity of NADPH oxidase was decreased, mitochondrial ROS production was reduced, malondialdehyde levels were lowered, glutathione peroxidase activity was increased; the proliferative ability of MBVSMCs was decreased, and the expression levels of molecules related to phenotypic transformation were altered. Furthermore, GATA3 promoted the expression of ring finger protein 34 (RNF34) of ubiquitin ligase, which in turn enhanced the ubiquitinated degradation of oxidative stress-related molecules and inhibited the phenotypic transformation of MBVSMCs, thereby exerting a protective effect on cerebrovascular remodeling. Collectively, these results suggest that GATA3 binds to RNF34 to augment its expression and accelerate the ubiquitinated degradation of oxidative stress-related molecules, thus exerting protective effects in IS.