Zheng Lemin's team discovered a new mechanism by which putrescine in smooth muscle cells promotes the development of abdominal aortic aneurysm

202 2 February 25 Zheng Lemin Group, Institute of Cardiovascular Research, School of Basic Medical Sciences The team published an online publication entitled "GasderminD deficiency in vascular smooth muscle cellsameliorates" in the internationally renowned journal Advanced Science Abdominal aortic aneurysm through reducing putrescine synthesis" paper reports that GSDMD can be accessed in aortic smooth muscle cells Promoting putrescine synthesis and aggravating the development of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a very dangerous aortic disease characterized by local irreversible dilation
of the abdominal aorta.
The team has combined non-targeted and targeted metabolomics in abdominal aortic aneurysm and dissection diseases to explore the disease-promoting effects of succinic acid in macrophages[1].

However, little is known about other cellular metabolism in the aorta
.
Loss and phenotypic conversion of Vascular smooth muscle cells (VSMCs) are the main pathological changes
that occur in AAA.
The team also found that the ANXA1 protein in aortic smooth muscle cells can inhibit the occurrence of aortic dissection [2].

It has been reported that gastrin protein D (GSDMD) is used as cell pyrosis in VSMC of aortic aneurysm and dissected vascular tissue Upregulation of protein expression is performed, but its mechanism of action remains unclear
.

Based on published single-cell data, the team found that in a model of aortic aneurysm and dissection induced by a high-fat diet combined with angiotensin II, the mRNA levels of GSDMD in aortic smooth muscle cells of diseased mice were higher than those in control mice
。 Thus, a VSMC-specific GSDMD knockout model of mice was established, and angiotensin II-induced AAA model, GSDMD, was observed The absence of AAA improved the occurrence and progression of AAA and promoted the transition
of VSMC to a contractile phenotype.

Using non-targeted metabolomics techniques, the team found a significant reduction
in putrescine in plasma and aortic tissue in VSMC-specific GSDMD-deficient mice.
Purescine is a type of biogenic amine produced by ornithine decarboxylase (ODC), which can be further metabolized to spermidine and spermine
.
High levels of putrescine expression
have been reported in tumors and other diseases.
In our experiment, the team studied putrescine levels in the plasma of 84 AAA patients and 95 healthy people and found that high levels of putrescine in plasma were associated with the risk of AAA (p<2.
2 x10-16).

High putrescine levels trigger a synthetic phenotype of VSMC and increase the susceptibility of mice to angiotensin II-induced AAA formation
.
The overexpression of putrescine enzyme ODC1 in the mouse aorta also promoted the occurrence and development of AAA, and the ODC1 inhibitor difluoromethylornithine (DFMO) was used Treatment reduces angiotensin II-induced AAA formation
.

Mechanistically, GSDMD enhances the PERK-eIF-2α pathway and activates endoplasmic reticulum stress-C/EBP homologous protein (CHOP) signaling, which in turn promotes Synthesis of ODC1.

By verifying the transcription factors C/EBPβ and NF-κB affected by putrescine, we proved that putrescine promotes the conversion of smooth muscle cells to synthetic type, while increasing the inflammatory level of smooth muscle cells, and ultimately promotes the development of AAA
。

Our results show that putrescine is a potential biomarker and target for AAA therapy, which provides new ideas and targets for the study of the metabolism-related mechanism of AAA
.
The laboratory looks forward to making greater breakthroughs
in the mechanism and treatment of aneurysms and dissections in the future.
Gao Jianing, a doctoral student at Peking University School of Basic Medical Sciences, and Chen Yanghui, a doctoral student at Wuhan Tongji Hospital of Huazhong University of Science and Technology, are the co-first authors of this paper and Professor Zheng Lemin of Peking University Wang Daowen, professor of Wuhan Tongji Hospital of Huazhong University of Science and Technology, is the corresponding author
of this article.
This work was supported by the National Natural Science Foundation of China and the Major Special Fund of the Ministry of Science and Technology.

Original link: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202204038

References

[1] Cui H, Chen Y, Li K, Zhan R, Zhao M, Xu Y, Lin Z, Fu Y, He Q, Tang PC, Lei I, Zhang J, Li C, Sun Y, Zhang X,Horng T, Lu HS, Chen YE, Daugherty A, Wang D, Zheng L.
Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.
EurHeart J.
2021 Nov 7; 42(42):4373-4385.

[2] Zhou C, Lin Z, Cao H, Chen Y, Li J, Zhuang X, Ma D, Ji L, Li W, Xu S, Pan B, Zheng L.
Anxa1 in smooth muscle cells protects against acute aortic dissection.
Cardiovasc Res.
2022 May 6; 118(6):1564-1582.

(School of Basic Medicine, Peking University)