March2 Alleviates Aortic Aneurysm/Dissection by Regulating PKM2 Polymerization
Yiran E. Li, Shuolin Liu, Litao Wang, Litao Wang, Yuxin Du, Lin Wu, Haoran Chen, Tingfang Zhu, Jie Lin, Shengjun Xiong, Yayu Wang, Qijun Zheng, Rongjun Zou, Ling Lin, Zheyun Li, Lixin Wang, Lixin Wang, Junbo Ge, Jun Ren, Yingmei Zhang
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: ) 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.