BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a kind of life-threatening cardiovascular condition with a poor prognosis, currently lacking effective drug therapies that can halt the progression of TAAD. Tirzepatide, a dual GIP and GLP-1 receptor agonist used for type 2 diabetes and weight management, has shown cardioprotective potential, yet its effect on TAAD remains unknown.
METHODS: A TAAD model in mice was developed by providing 0.5% β-aminopropionitrile (BAPN) for 28 days.Mice were categorized into control, tirzepatide-only, BAPN, and BAPN combined with tirzepatide.Tirzepatide (10 nmol/kg) was administered daily via intraperitoneal injection. Aortic morphology, incidence of TAAD, medial degeneration, inflammation, elastin integrity, and proteoglycan deposition were assessed by gross examination and histological analyses. Inflammatory cells infiltration and signaling pathways were evaluated by immunostaining and western blotting. In parallel, platelet-derived growth factor-BB (PDGF-BB) stimulated human aortic smooth muscle cells (HASMCs) were used as an in vitro model to examine the direct effects of TZP on VSMC phenotypic modulation.
RESULTS: Treatment with tirzepatide led to a significant reduction in both the formation of TAAD (from 88.9% to 50.0%) and related deaths (from 83.3% to 38.9%). It also effectively suppressed the pathological expansion of the aortic diameter in the ascending, arch, and descending regions. Histological analysis revealed improved elastic fiber integrity and reduced degradation. Tirzepatide prevented VSMC phenotypic switching, reduced inflammatory cells infiltration, and lowered IL-1β, IL-6, and MCP-1 levels. It also downregulated NLRP3 and caspase-1 expression. In vitro, TZP directly reversed PDGF-BB-induced downregulation of VSMC contractile markers (MYH11, SMA, SM22, and CNN1) and mitigated cytoskeletal and morphological changes associated with phenotypic switching.
CONCLUSION: Our findings indicate that tirzepatide curbs the development of TAAD in mice. The underlying mechanism likely involves the suppression of the NLRP3 inflammasome priming, a consequent reduction in vascular inflammation, and the preservation of the contractile state of VSMC. These findings highlight its potential as a novel therapeutic strategy for TAAD.
