Our study provides compelling evidence that SAM treatment effectively slows down the progression of thoracic aortic dissection (TAD) in a BAPN-induced TAD model. This research represents the first investigation into SAM's potential role in TAD progression through nutritional intervention. The evidence presented, which includes improved survival rates, reduced incidence of TAD formation and rupture, as well as diminished degradation of elastin fibers and collagen, along with attenuated leukocyte infiltration, strongly supports the effectiveness of SAM intervention in TAD progression. Moreover, our findings suggest that SAM exerts its beneficial effects by mitigating macrophage M1 polarization and T cell activation, which ultimately contributes to the reduction in elastin and collagen degradation. This study underscores the critical role of SAM in TAD progression and highlights a promising nutritional intervention strategy for TAD prevention.
Methionine adenosyltransferase 2A (MAT2A) stands as a pivotal enzyme in the methionine cycle, chiefly orchestrating the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP)41. A growing body of evidence suggests that mutations in MAT2A render individuals more susceptible to thoracic aortic disease42. SAM, serving as a vital substrate for methyl transfers to various biomolecules, undergoes a cyclical transformation that produces S-adenosylhomocysteine (SAH). The hydrolysis of SAH then yields homocysteine and adenosine, ultimately leading to the regeneration of methionine and SAM. The balance between SAM and SAH, reflected in the SAM/SAH ratio, is crucial for maintaining appropriate cellular methylation dynamics43.
Notably, plasma SAH has been positively linked to the risk of cardiovascular events, independent of plasma total homocysteine concentrations, especially in patients undergoing coronary angiography44. Previous studies have unveiled associations between elevated plasma SAH concentrations and endothelial dysfunction, atherosclerosis, involving mechanisms such as oxidative stress45, 46 and endoplasmic reticulum stress47. SAM, known for its role in regulating methylation reactions and influencing gene expression in various diseases23, 48, has been the focus of several retrospective studies in cardiovascular disease (CVD) patients. These studies indicated a decrease in plasma SAM in CVD patients, a positive association with flow-mediated vasodilation (FMD), and an inverse correlation with carotid intima-media thickness (IMT)49–51. Additionally, exogenous SAM supplementation has demonstrated promising outcomes by reducing injury-induced carotid intima thickness and enhancing endothelium-dependent vasodilation in mice52, 53. However, conflicting reports have surfaced, with some studies suggesting increased or unchanged plasma SAM in patients with CVD54, 55. Considering SAM's crucial role as a methyl donor in virtually all cellular methylation reactions, its deficiency has been associated with abnormal DNA methylation in CVD, as noted in previous case-control studies55. Consequently, we formulated a hypothesis positing an inverse association between SAM and the risk of CVD. In this study, we embarked on a prospective evaluation of the relationship between SAM supplementation and the risk of TAD in a mouse model. In corresponding with previous study, SAM supplementation significantly decreased the incidence and mortality of TAD.
Examining the intricate connection between methionine metabolism and T cell function reveals a complex interplay that can be harnessed for potential immunomodulation strategies. Higher levels of S-adenosylmethionine (SAM) are linked to a diminished anti-tumor effector function in CD8 + T cells, influencing the histone methylation landscape and suppressing the expression of critical effector genes56. Strategically inhibiting the methionine cycle through methionine restriction could potentially enhance the anti-tumor response of CD8 + T cells by inducing epigenetic reprogramming. Additionally, S-adenosylhomocysteine (SAH), a byproduct of SAM, could play a pivotal role in modulating T cell responses. SAH hydrolase (SAHH) promotes the effector function of pro-inflammatory CD4 + T cells, while its product, homocysteine, supports the proliferation and effector function of T cells57, 58. This raises the intriguing possibility that SAHH overexpression might augment the anti-tumor effector function of T cells. Interestingly, ethanol-induced suppression of MAT2A expression in CD4 + T cells, resulting in decreased SAM levels and increased T cell activation-induced apoptosis, highlights the critical role of SAM in T cell survival during activation16. Conversely, in T cells deficient in autophagy, reduced SAM levels were associated with altered histone methylation patterns, increased expression of effector genes, and enhanced anti-tumor function of CD8 + T cells56. This intriguing duality suggests that SAM, under specific metabolic conditions, may exert suppressive functions through the regulation of histone methylation. The role of SAH, generated from SAM by methyltransferases, in regulating the effector function of CD4 + T cells adds another layer of complexity. SAHH inhibitors have shown promise in modulating inflammatory T cells and regulatory T cells in various mouse models, indicating potential therapeutic applications59–61. In summary, the interplay between methionine metabolism and T cell function presents a complex landscape with potential implications for immunomodulation. In our study, we detected decreased CD4 + T cells and CD8 + T cells activation which is demonstrated by decreased CD44 + CD62L- effector T cells proportion and increased CD44- CD62L + naive T cells. However, the precise mechanism by which SAM influences the activation of T cells remains to be fully elucidated, warranting further investigation.
A previous investigation explored the effects of SAM on cytokine expression in human THP1 macrophage cells, suggesting its involvement in genome-wide and gene-specific epigenetic modifications. The study proposed that SAM could rapidly influence epigenetic gene regulation within 24 hours of exposure, affecting the expression of genes encoding specific inflammatory mediators. Our current study provides further support for these findings, demonstrating a significant reduction in BAPN-induced expression of proinflammatory cytokines TNFα and IL1β by SAM, indicating its broad-ranging impact on inflammation. These results are consistent with earlier research demonstrating SAM's anti-inflammatory effects in murine macrophages within a BAPN-induced aortic dissection model62, 63.
Although our research sheds light on the role of SAM in TAD progression through in vivo experiments, uncertainties linger regarding its corresponding role in in vitro cell experiments. The complexities of SAM regulation in TAD, involving immune cells, inflammation-related factors, and VSMCs, pose challenges in conducting meaningful in vitro studies. Furthermore, our deliberate decision to utilize male mice aimed to reduce hormonal variability, suggesting that the results may not directly translate to female mice. Nonetheless, our findings strongly underscore SAM's pivotal role in improving TAD outcomes.
To summarize, our study presents compelling evidence supporting the protective effects of SAM in TAD development. SAM treatment effectively mitigates leukocyte infiltration, particularly macrophages and neutrophils, reduces aortic inflammation, and suppresses T cell activation, ultimately contributing to the attenuation of TAD progression. These results position SAM as a promising and effective strategy for both the prevention and treatment of TAD.