Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease without effective pharmacological therapies. Mounting evidences suggested that RNA-binding proteins (RBPs) exert pivotal roles in various diseases including AAA. The public human AAA microarray dataset and the RBP database were used to screen the involved RBPs during AAA formation. The integrated analysis identified zinc finger protein 36 (ZFP36) as a potential mediator of AAA. Underexpression of ZFP36 was observed in aortic vascular smooth muscle cells (VSMCs) within aneurysms from patients and angiotensin II (AngII)-induced mice. Zfp36 deficiency in VSMCs augmented extracellular matrix (ECM) degeneration, VSMC phenotypic switch, and apoptosis, which promoted AAA formation in the AngII-infused model. In contrast, VSMC-specific overexpressing Zfp36 inhibited AAA formation. Mechanically, guanylate binding protein 2 (GBP2), a GTPase related to interferon-γ signaling, was identified as a direct target gene of ZFP36 by analyzing the bulk sequencing data. We confirmed that ZFP36 regulates VSMC phenotypic switch via manipulating Yes-associated protein1/TEA domain transcription factor 1 (YAP1/TEAD1) signaling in a GBP2-dependent manner. Additionally, we further verified that dexamethasone (Dex) could promote glucocorticoid receptor nuclear translocation and Zfp36 transcription. In vivo Dex administration prevented AAA formation in a ZFP36-dependent manner. These findings revealed the regulatory role of ZFP36/GBP2/YAP1/TEAD1 signaling in VSMC phenotypic switch and AAA formation, and provided a novel strategy (Dex) for AAA treatment.