Gasdermin D deficiency attenuates development of ascending aortic dissections in a novel mouse model.

Abstract

Thoracic aortic dissection (TAD) is a silent killer. Approximately two-thirds of the cases occur in the ascending aorta (i.e. type A dissection) and majority of them are unrelated to genetic mutations. However, animal models of spontaneous type A dissection are not widely available. In the present study, a novel mouse TAD model was created. Further, the role of gasdermin D (GSDMD) in TAD development was evaluated. TADs were created by treating ascending aorta of adult mice (C57BL/6J) with active elastase (40.0 U/ml) and β-aminopropionitrile (Act E+BAPN). The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms explored with bulk RNA sequencing of specimens collected at multiple timepoints. With this novel TAD model, further experiments were performed with Gsdmd -/- mice to evaluate its impact on TAD formation. The ascending aorta challenged with Act E+BAPN developed pathology characterized by an early onset of intimomedial tears (complete penetration) and intramural hematoma, followed by progressive medial loss and aortic dilation. Ingenuity Pathway Analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory micro-environment, rather than general inflammation, promoted the onset of TADs by specifically recruiting neutrophils to the aortic wall, while the pathology at the advanced stage was driven by T-cell mediated immune injury. Gsdmd -/- attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect was associated with a reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) positive cells and T-cells in TADs. A novel mouse TAD model was created in the ascending aorta. It produces a unique microenvironment to activate different immune cell subsets, promoting onset and subsequent remodeling of TADs. Consistently, Gsdmd -/- attenuates TAD development, with modulation of cell death and T-cell response likely acting as the underlying mechanism.