Impaired S181 phosphorylation of RBM24 leads to cardiac contractile dysfunction, atrial fibrillation, and sudden death under psychological stress by inhibiting APOE translation.
RBM24-S181 phosphorylation links psychological stress to cardiovascular disease via eIF4E-regulated APOE translation, offering a potential therapeutic target and biomarker.
Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD. Mental stress is well known to cause cardiovascular disease. Here, the authors show that an imbalance in RBM24-S181 phosphorylation impairs cardiac translation of APOE, leading to cardiac contractile dysfunction, atrial fibrillation, fibrosis, and sudden death under psychological stress.
He et al. (Sat,) conducted a other in Psychological stress-induced cardiovascular disease. Rbm24 S181A mutation and psychological stress vs. Wild-type and non-stress conditions was evaluated on Cardiac contractile dysfunction, electrophysiological abnormalities, and survival. Impaired S181 phosphorylation of RBM24 leads to cardiac contractile dysfunction, atrial fibrillation, and sudden death under psychological stress by inhibiting APOE translation.