Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-β Pathway.

Tzu-Heng Huang,Wei-Chiao Chang,Yi-Fan Chen,Yu-Ru Guo,Hsiao-Huang Chang

doi:10.3390/ijms222111737

Abstract

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor β (TGF-β) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

Highlights

Marfan syndrome (MFS) is an inherited connective tissue disorder that is often caused by the mutation of fibrillin 1 (Fbn1) and the consequent extracellular matrix (ECM) degeneration [1,2]
This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients
thoracic aortic aneurysm (TAA) Was Associated with Insufficient Smad4, Mtr, and Mtrr in Fbn1C1039G/+ (MFS) Mice

Summary

Introduction

Marfan syndrome (MFS) is an inherited connective tissue disorder that is often caused by the mutation of fibrillin 1 (Fbn1) and the consequent extracellular matrix (ECM) degeneration [1,2]. Researchers have studied different aspects of MFS pathology for decades to explore personalized therapies [4,5]. It has been assumed for a long time that Transforming growth factor β (TGF-β) signaling plays a central role in MFS pathology. The canonical TGF-β signaling pathway, on the other hand, plays an entirely different role in TAA pathology. The upregulation of the Smad4-dependent TGF-β signaling pathway in SMCs protected against aortic aneurysm formation and dissection. Recent studies showed that the expression of lysyl oxidases, downstream of both canonical and noncanonical TGF-β pathways, was highly correlated with the pathogenesis of TAA. In an MFS mouse model, the inhibition of Lox by β-aminopropionitrile (BAPN) rapidly caused aortic disintegration and dissection; lysyl oxidases reserved aortic integrity by promoting ECM maturation and cross-linking [15]

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Conclusion