Acute aortic dissection can be caused by DNA methylation

Acute aortic dissection (AAD) is a serious cardiovascular condition that involves tears in the main artery's inner layer and can be life-threatening. In the Stanford classification of aortic dissection, type A involves the ascending aorta and could progress to the arch and thoracoabdominal aorta. Stanford-A AAD is the most frequent type that accounts for almost 75% of AAD cases and is characterized by sudden onset, quick progression, and poor prognosis. The genetic factor is the leading risk factor for AAD development. But genes are not the only reason, as DNA methylation was proven to be associated with the development of AAD in a recent study.

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Epigenetic changes such as DNA methylation regulate gene expression without altering the genomic sequences. To learn more about epigenetic alterations, you can read more in our articles. DNA methyltransferases (DNMTs) mediate DNA methylation. DNA hypermethylation could reduce the gene promotor's transcription activity and lead to gene silencing. The research group of Chen et al. found out in their previous study that the levels of two DNA methyltransferases: DNMT1 and DNMT3B, decreased visibly in AAD samples. In contrast, the expression of two others called DNMT3a and DNMTL had decreased, indicating the potential role of DNA methylation in AAD. Chen`s group designed a two-stage study to explore the DNA methylation profiles of AAD. The first stage, called the discovery stage, included 4 AAD patients and 4 healthy controls. The second stage, or the replication stage, consisted of 16 AAD patients and 7 healthy controls. They were independent of the patients in the first stage. 

A total of 589 differentially methylated positions were found in the AAD group: 315 hypomethylated and 274 hypermethylated. The differentially methylated position-associated genes were enriched in processes such as:

• the MAPK signaling pathway,
• TNF signaling pathway,
• apoptosis pathway,
• protein binding,
• angiogenesis,
• heart development.

The differential DNA methylation in five key genes was authenticated in the independent replication cohort. Those genes included:

• Fas which plays a significant role in apoptosis
• ANGPT2 coding Angiopoietin-2, involved in the regulation of angiogenesis and inflammation
• DUSP6 coding enzyme Dual specificity phosphatase 6
• FARP1  coding proteins f.ex pleckstrin
• CARD6, which modulates NF-κB signaling pathway

The protein expression level of the Fas was 1.78 times higher, indicating the possible role of DNA methylation in regulating gene expression.

The described study has some limitations, such as small sample sizes and sample heterogeneity. Therefore, DNA methylation in AAD and other cardiovascular conditions needs to be more thoroughly studied. Nevertheless, the study's results highlight the importance of epigenetic alterations as a mechanism of aging and disease.

Source: Chen Y, Xu X, Chen Z, Huang B, Wang X, Fan X. DNA methylation alternation in Stanford- A acute aortic dissection. BMC Cardiovasc Disord. 2022;22(1):455