Keywords

1. Thoracic Aortic Aneurysm
2. Estrogen Receptor 1
3. MDM2
4. Macrophage Migration Inhibitory Factor
5. Vascular Smooth Muscle Cell Dedifferentiation

New Research Sheds Light on the Molecular Dynamics of Thoracic Aortic Aneurysm Progression and Potential Intervention Targets

In a groundbreaking study recently published in the [Biochimica et Biophysica Acta Molecular Cell Research journal](https://doi.org/10.1016/j.bbamcr.2024.119661), scientists have unveiled a novel mechanism involved in the progression of thoracic aortic aneurysm (TAA), an often lethal condition characterized by the abnormal dilation of the aorta. The research, led by Liu Tao and Zhang Tian at Guangxi Medical University in China, identifies the degradation of estrogen receptor 1 (ESR1) mediated by murine double minute 2 (MDM2) as a key event that activates macrophage migration inhibitory factor (MIF), thereby promoting the dedifferentiation of vascular smooth muscle cells (VSMCs) and contributing to oxidative stress within the aortic wall.

Thoracic Aortic Aneurysm: A Silent Killer

TAAs are life-threatening and often go undetected until they become symptomatic or result in catastrophic aortic dissection or rupture. Affecting up to 10.4 in every 100,000 individuals each year, TAAs are a significant cause of morbidity and mortality. Despite advances in surgical techniques and diagnostic approaches, the molecular mechanisms underpinning TAA pathogenesis have not been fully elucidated. Understanding these mechanisms is crucial for identifying biomarkers and developing novel therapeutic strategies.

Estrogen Receptor 1: From Biomarker to Therapeutic Target

ESR1 has emerged as a potential biomarker for TAA, suggesting a role for estrogen signaling in TAA pathophysiology. The recent study underlines ESR1’s involvement in maintaining aortic integrity. Employing ApoE-knockout mice and cultured primary mouse VSMCs, the researchers established models to investigate the progression of TAA in the presence of angiotensin II (Ang II), a peptide known to contribute to aortic aneurysms.

Deciphering ESR1’s Protective Role in TAA

Upon Ang II induction, ESR1 expression was found to be downregulated in both TAA mice and VSMCs. The upregulation of ESR1, conversely, had a protective effect, mitigating aortic expansion, cell apoptosis, the pathogenetic transformation of VSMCs, inflammatory infiltration, and oxidative stress. The study highlights ESR1 as not just a mere marker but a protective component against aneurysm deterioration.

MDM2: The Mediator of ESR1 Degradation

Liu Tao’s team delved deeper into the ESR1 pathway and identified MDM2 as a critical player in ESR1 regulation. In the context of TAA, MDM2 expression was elevated, facilitating the ubiquitination and subsequent degradation of ESR1. Inhibiting MDM2 in their models led to reduced VSMCs dedifferentiation and suppressed oxidative stress, implicating MDM2 as a promoter of TAA progression via ESR1 degradation.

Macrophage Migration Inhibitory Factor: The Missing Link

Macrophage migration inhibitory factor, a vital inflammatory mediator, emerged from the study as an important biological target modulated by the ESR1-MDM2 axis. ESR1 binds to the MIF promoter, repressing its transcription. The artificially induced restoration of MIF reversed the beneficial effects mediated by ESR1 overexpression, reinforcing the role of ESR1 in modulating MIF and influencing TAA progression.

Clinical Implications and Future Perspectives

This research illuminates previously obscured facets of the molecular pathophysiology of TAAs. By identifying ESR1 as a vital protective factor and unveiling the MDM2-MIF pathway as a key contributor to the disease’s progression, Liu Tao’s team paves the way toward targeted therapies that can potentially slow down or even reverse the growth of aortic aneurysms.

The implications for clinical practice are substantial. As we now understand the MDM2-induced degradation of ESR1 as a crucial step in TAA progression, medical interventions aimed at stabilizing ESR1 or disrupting MDM2’s ability to target it for destruction could hold therapeutic promise. Likewise, the modulation of MIF stands as a viable strategy for mitigating the exacerbation of TAA.

Future studies are crucial to explore the translational potential of these findings. Specific MDM2 inhibitors or gene therapy to boost ESR1 levels in VSMCs present exciting avenues for therapeutic development. Moreover, refining our understanding of the MDM2-ESR1-MIF axis could lead to personalized medicine approaches, wherein patients with TAAs are assessed and treated based on their molecular profiles.

Community and Expert Reactions

The scientific community has received this groundbreaking work with enthusiasm, signaling a potential sea change in the approach to cardiovascular research and TAA management. Dr. Wang Pandeng, one of the study’s co-authors, urges for prompt personal and collective action, highlighting the need for “further research to explore the clinical applicability of these findings and the development of novel therapeutic agents.”

Conflict of interest disclosures indicate no competing financial interests or personal relationships that could bias the work, as declared by the authors. This transparency adds to the credibility and scientific integrity of the research.

This pioneering study not only offers new insights into TAA pathology but also drives home the critical role of molecular research in combatting cardiovascular diseases. As researchers and clinicians forge ahead, empowered by these findings, there is a renewed hope for better outcomes for individuals afflicted with this insidious condition.

References

1. Liu T., Zhang T., Guo C., Liang X., Wang P., Zheng B. (2024) Biochimica et Biophysica Acta Molecular Cell Research, Murine double minute 2-mediated estrogen receptor 1 degradation activates macrophage migration inhibitory factor to promote vascular smooth muscle cell dedifferentiation and oxidative stress during thoracic aortic aneurysm progression. DOI: [10.1016/j.bbamcr.2024.119661] 2. Goldfinger J.Z., Halperin J.L., Marin M.L., Stewart A.S., Eagle K.A., Fuster V. (2011). Thoracic aortic aneurysm and dissection. J. Am. Coll. Cardiol. 58(21): e123–e163. PMID: 22112971.
3. Milewicz D.M., Dietz H.C., Miller D.C. (2005). Treatment of aortic disease in patients with Marfan syndrome. Circulation. 111(11): e150–e157. PMID: 15781745.
4. Humphrey J.D., Schwartz M.A., Tellides G., Milewicz D.M. (2015). Role of mechanotransduction in vascular biology: Focus on thoracic aortic aneurysms and dissections. Circ. Res. 116(8): 1448-1461. PMID: 25858065.
5. Hiratzka L.F., Bakris G.L., Beckman J.A., Bersin R.M., Carr V.F., Casey D.E. Jr., et al. (2010). Guidelines for management of patients with thoracic aortic disease. Circulation. 121(13): e266–e369. PMID: 20233780.

About the Authors

Liu Tao, T., Zhang Tian, T., Guo Chenfan, C., Liang Xiangsen, X., Wang Pandeng, P., & Zheng Baoshi, B. (2024). The collaborative team comes from the Department of Cardiothoracic Surgery and the Department of Cardiovascular Surgery at the First Affiliated Hospital of Guangxi Medical University and the Guangxi International Zhuang Medicine Hospital linked with Guangxi University of Chinese Medicine. With a joint mission, these researchers have combined their expertise in clinical practice and molecular research to unravel the complexities of thoracic aortic aneurysm progression, offering new hope in the fight against this challenging disease.