Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice

Ze Long, Liu, Yan, Li, Yi Jun, Lin, Mao Mao, Shi, Meng Xia, Fu, Zhi Qing, Li, Da Sheng, Ning, Xiang Ming, Zeng, Xiang, Liu, Qing Hua, Cui, Yue Ming, Peng, Xin Min, Zhou, Ye Rong, Hu, Jia Sheng, Liu, Yu Jia, Liu, Mian, Wang, Chun Xiang, Zhang, Wei, Kong, Zhi Jun, Ou, Jing Song, Ou

Nature Communications |

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates β-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-β signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.