Ythdc1-p300-Klf5 Complex-Mediated Golgi Dysfunction Promotes Aortic Aneurysm

Klf5 and Golph3l-mediated regulation of Golgi morphology has been implicated in the apoptosis of vascular smooth muscle cells (VSMCs), which leads to aortic wall thinning and aneurysm. However, the molecular link between Klf5, Golph3l, and Golgi morphology alteration in the context of the aneurysm is unclear. Here, we show that apoptosis-induced proliferation (AIP) in VSMCs occurs in aortic dissection (AD) and aortic aneurysm of humans and mice. Golph3l upregulation by Klf5 facilitates TNF-α and TNFSF12 secretion from AngII-stimulated VSMCs by inducing Golgi compaction, which is essential for AIP and aneurysm development. Mechanistically, AngII-induced elevation of global m6A RNA level, especially m6A-Gm40097, is responsible for Golph3l upregulation and AIP in VSMCs. Further, m6A-Gm40097 mediates Klf5 interaction with Ythdc1 and p300 to form a transcription complex on the Golph3l promoter, thus activating transcription. Finally, a predictive website for post-operative short-term death is built based on AD patient's features, providing a platform to be able to predict risk stratification of AD patients. Collectively, this study identifies a novel lncRNA m6A modification-dependent regulatory mechanism of chromatin remodeling and transcription activation. Targeting the Ythdc1-p300-Klf5 complex may serve as potential therapeutic strategy to improve Golgi dysfunction and aortic aneurysm.