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. 2025 Apr 11;136(8):e73-e93.
doi: 10.1161/CIRCRESAHA.124.325049. Epub 2025 Mar 13.

March2 Alleviates Aortic Aneurysm/Dissection by Regulating PKM2 Polymerization

Yiran E Li #  1   2   3   4   5 , Shuolin Liu #  1   2   6   3   4   5 , Litao Wang #  1   2   3   4   5 , Yuxin Du #  1   2   3   4   5 , Lin Wu  1   2   3   4   5 , Haoran Chen  1   2   3   4   5 , Tingfang Zhu  1   2   3   4   5 , Jie Lin  1   2   3   4   5 , Shengjun Xiong  1   2   3   4   5 , Yayu Wang  7   8 , Qijun Zheng  7 , Rongjun Zou  9 , Ling Lin  1   2   3   4   5 , Zheyun Li  2   6   10 , Lixin Wang  2   6   10 , Junbo Ge  1   2   3   4   5 , Jun Ren  1   2   3   4   5 , Yingmei Zhang  1   2   3   4   5
Affiliations

March2 Alleviates Aortic Aneurysm/Dissection by Regulating PKM2 Polymerization

Yiran E Li et al. Circ Res. .

Abstract

Background: Aortic aneurysm/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the E3 ubiquitin ligase March2 (membrane-associated RING [really interesting new gene] finger protein 2) to the cause of AAD remains elusive.

Methods: Integrated single-cell RNA sequencing analysis was conducted in human AAD tissues. Based on the screening results, we generated a mouse line of smooth muscle cell-specific March2 knockout. β-Aminopropionitrile monofumarate was used to establish AAD. Cleavage under targets and tagmentation and cleavage under targets and tagmentation-quantitative polymerase chain reaction were performed to identify possible target genes for histone H3K18 lactylation.

Results: March2 expression was downregulated in aorta from patients with AAD or β-aminopropionitrile monofumarate-induced AAD mice. β-Aminopropionitrile monofumarate-induced AAD was significantly accentuated in March2 global (March2-/-) and vascular smooth muscle cell-specific deletion (March2fl/fl; TaglnCre) mice, whereas the AAD pathology was rescued by rAAV9-SM22α (smooth muscle 22α)-March2 (recombinant adeno-associated virus serotype 9 expressing Flag-tagged March2 under SM22α promoter). March2 interacted with PKM2 (pyruvate kinase M2) to promote K33-linked polyubiquitination. Deficiency of March2 lessened PKM2 dimer-to-tetramer conversion in AAD and overtly exacerbated AAD-induced histone H3K18 lactylation in vascular smooth muscle cells by fostering glucose metabolism reprogramming, thereby promoting p53-driven apoptotic transcriptional response-a hallmark of AAD pathogenesis. TEPP-46 (tetraethyl pyrophosphate), a PKM2-specific activator, pronouncedly alleviated March2 deficiency-deteriorated AAD pathology.

Conclusions: Our findings demonstrated that March2 is a novel endogenous defender that prevents AAD by inhibiting vascular smooth muscle cell apoptosis, suggesting that March2 represents a potential therapeutic target for AAD.

Keywords: aminopropionitrile; aortic aneurysm; aortic dissection; cardiovascular diseases; ubiquitin.

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Conflict of interest statement

None.

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