Thoracic aortic aneurysms and dissections (TAADs) are life-threatening conditions with limited pharmacological options, often necessitating high-risk surgical repair.² A key pathological feature is aortic medial degeneration, marked by the accumulation of a glycan-rich matrix. A new study published in the European Heart Journal has identified a metabolic pathway that drives this process, suggesting a novel therapeutic target for both genetic and sporadic forms of TAAD.¹
The study focused on the hexosamine biosynthetic pathway (HBP), a metabolic route that produces substrates for glycosylation. Researchers hypothesised that overactivation of the HBP triggers the integrated stress response (ISR), a cellular mechanism that, under chronic stress, can lead to vascular smooth muscle cell dysfunction and contribute to aneurysm formation.
Investigators analysed HBP activation using transcriptomic and metabolomic approaches in aortic tissue from multiple sources. These included a mouse model of Marfan syndrome (MFS), the most common inherited disorder associated with TAAD; a non-genetic mouse model of TAAD induced by β-aminopropionitrile; and aortic samples from patients with sporadic TAAD and MFS. The therapeutic potential of targeting this pathway was assessed by pharmacologically inhibiting HBP and ISR in the MFS mouse model, with aortic dilatation monitored by ultrasound.
The results showed that the HBP was significantly upregulated across all models of TAAD, including in aortic samples from both MFS and sporadic TAAD patients. This enhanced HBP activity was found to directly contribute to aortic dilatation and medial degeneration. Furthermore, the study demonstrated that this pathological process was mediated by the activation of the ISR. In the MFS mouse model, pharmacological inhibition of either the HBP or the ISR successfully reversed aortic dilatation and medial degeneration, restoring aortic homeostasis.
These findings highlight a crucial link between cellular metabolism and the structural integrity of the aortic wall. The study concludes that "the HBP–ISR axis drives medial degeneration in TAAD," identifying this axis as "a potential target in TAAD of both genetic and non-genetic origin."¹ Targeting this pathway could offer a new therapeutic strategy to slow or reverse the progression of aortic aneurysms, potentially reducing the need for surgical intervention. The researchers also noted that circulating HBP metabolites were elevated in MFS patients, suggesting their potential use as biomarkers for the disease.
The authors suggest that further research is warranted to develop selective inhibitors for this pathway and to fully elucidate the specific roles of different types of glycosylation in the development of TAAD.
This study was funded by the Conchita-Rábago Foundation, Spanish Ministerio de Ciencia e Innovación, European Research Council, Instituto de Salud Carlos III, and La Caixa Foundation.
References
1. Rochano-Ortiz A, San Sebastián-Jaraba I, Zamora C, et al. Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response. Eur Heart J 2025;46:4988–5005. https://doi.org/10.1093/eurheartj/ehaf556
2. Goldfinger JZ, Halperin JL, Marin ML, et al. Thoracic aortic aneurysm and dissection. J Am Coll Cardiol 2014;64:1725–39. https://doi.org/10.1016/j.jacc.2014.08.025
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