ZFP36 Protects against Abdominal Aortic Aneurysm Formation by Regulating Vascular Smooth Muscle Phenotypic Switch

Area of Science:

• Vascular Biology
• Molecular Medicine
• Genetics

Background:

• Abdominal aortic aneurysm (AAA) is a serious condition lacking effective drug treatments.
• RNA-binding proteins (RBPs) are implicated in various diseases, including AAA.
• Identifying key RBPs involved in AAA pathogenesis is crucial for therapeutic development.

Purpose of the Study:

• To investigate the role of RNA-binding proteins (RBPs) in abdominal aortic aneurysm (AAA) formation.
• To identify specific RBPs that mediate AAA pathogenesis.
• To explore potential therapeutic strategies targeting identified RBPs for AAA treatment.

Main Methods:

• Integrated analysis of human AAA microarray data and RBP databases to screen for involved RBPs.
• In vitro and in vivo studies using angiotensin II (AngII)-induced mouse models to assess the function of zinc finger protein 36 (ZFP36).
• Analysis of bulk sequencing data to identify direct target genes of ZFP36 and elucidation of downstream signaling pathways.

Main Results:

• Zinc finger protein 36 (ZFP36) was identified as a key mediator in AAA.
• ZFP36 underexpression in vascular smooth muscle cells (VSMCs) exacerbated extracellular matrix degeneration and promoted AAA formation.
• ZFP36 regulates VSMC phenotypic switch via the guanylate binding protein 2 (GBP2)/Yes-associated protein1/TEA domain transcription factor 1 (YAP1/TEAD1) signaling pathway.
• Dexamethasone (Dex) administration upregulated ZFP36 and prevented AAA formation in vivo.

Conclusions:

• ZFP36 plays a critical protective role in preventing AAA formation by regulating VSMC phenotype.
• The ZFP36/GBP2/YAP1/TEAD1 signaling axis is a key regulator of VSMC phenotypic switch in AAA.
• Dexamethasone represents a promising therapeutic strategy for AAA by modulating ZFP36 expression.