Stachydrine alleviates thoracic aortic aneurysm via regulating lactate dehydrogenase A in Marfan syndrome mice.

BACKGROUND

Marfan syndrome (MFS) is a genetic disorder predominantly caused by mutations in the FBN1 gene, leading to thoracic aortic aneurysm (TAA) and a lack of effective pharmacological treatments. However, the role of metabolic alterations in this process remains poorly understood.

PURPOSE: We aim to investigate the regulatory roles of metabolites in MFS.

METHODS

Fbn1C1039G/+ mice were utilized as a TAA mouse model of MFS. Untargeted metabolomic screening of aortic tissues was conducted to identify metabolites in Fbn1C1039G/+ mice compared to controls. Echocardiographic and EVG staining were performed to evaluate TAA. Vascular smooth muscle cells (VSMCs) were isolated from mice for in vitro experiments. Proteomic sequencing was conducted to identify target mediators. Rescue experiments were carried out using recombinant LDHA in vitro.

RESULTS

Stachydrine (STA) was upregulated in Fbn1C1039G/+ mice aorta compared with controls. Administration of STA notably mitigated thoracic aortic dilation and medial degeneration in MFS mice. Furthermore, STA significantly diminished the elevated expression of matrix metalloproteinases and the excessive activation of the transforming growth factor-β (TGF-β) signaling pathway in vivo and in vitro. Proteomic analysis revealed that STA treatment led to a reduction in lactate dehydrogenase A (LDHA) expression. Rescue experiments further confirmed that LDHA acts as a critical mediator downstream of STA.

CONCLUSIONS

STA attenuated TAA in MFS by inhibiting LDHA, thereby modulating TGF-β signaling and maintaining extracellular matrix homeostasis. These findings highlight STA as a protective metabolite and suggest LDHA as a potential therapeutic factor for TAA in MFS.