Family-Wide Dysregulation of Phosphodiesterases Alters cAMP/cGMP Microdomains in Thoracic Aortic Aneurysm

TL;DR

This study finds that multiple phosphodiesterase enzymes are dysregulated in thoracic aortic aneurysm, with PDE10A showing potential as a biomarker and therapeutic target.

Contribution

The study identifies family-wide PDE dysregulation in TAA and highlights PDE10A as a novel biomarker and therapeutic target.

Findings

Thirteen PDE isoforms were significantly dysregulated in TAA, with PDE10A showing excellent discrimination (AUC = 0.838).

PDE subfamilies showed coordinated regulation, including inverse relationships like PDE2A and PDE8B (r = −0.68).

PDE dysregulation is linked to endothelial barrier fragility and maladaptive smooth-muscle remodeling in TAA.

Abstract

Background: Thoracic aortic aneurysm (TAA) is driven by complex molecular mechanisms beyond size thresholds, yet the role of cyclic nucleotide metabolism remains unclear. Phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP in compartmentalized microdomains, act as key regulators of vascular integrity and remodeling. Methods: We performed a hypothesis-driven, transcriptomic analysis of 20 PDE isoforms using the GSE26155 dataset (43 TAA vs. 43 controls). Raw microarray data underwent background correction, log2 transformation, and false-discovery adjustment. Differential expression, logistic regression, receiver-operating characteristic (ROC) curves, calibration testing, correlation analysis, and interactome/enrichment mapping were conducted. Results: Thirteen PDE isoforms were significantly dysregulated in TAA. Upregulated transcripts included PDE10A, PDE2A, PDE4B, PDE7A, and PDE8A, whereas PDE1A/B/C, PDE3B, PDE5A, PDE6C, and PDE8B were downregulated. PDE10A achieved excellent discrimination for TAA (AUC = 0.838), while other isoforms demonstrated fair discriminatory ability. Correlation architecture revealed coordinated regulation between PDE subfamilies, including inverse relationships between PDE2A and PDE8B (r = −0.68). Interactome analysis highlighted dense connections with cyclic nucleotide and purinergic signaling hubs, enriched in vascular tone, NO–cGMP–PKG, and junctional assembly pathways. Integrating these findings with epigenetic and junctional frameworks suggests that PDE dysregulation promotes endothelial barrier fragility and maladaptive smooth-muscle remodeling. Conclusions: Family-wide PDE dysregulation characterizes human TAA, with PDE10A emerging as a central transcriptomic signature. Altered cAMP/cGMP microdomain signaling aligns with junctional failure and epigenetic control, supporting the potential of PDE isoforms as biomarkers and therapeutic targets. These results provide experimental evidence that cyclic nucleotide hydrolysis is re-wired in TAA, supporting PDE10A as a novel biomarker and therapeutic target that bridges molecular dysregulation with clinical risk stratification in thoracic aortic disease.

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