Ythdc1-p300-Klf5 complex-mediated Golgi dysfunction promotes aortic aneurysm

Klf5 and Golph3l-mediated regulation of Golgi morphology has been implicated in the development of apoptosis induced by diverse stress stimuli, and the loss of VSMCs caused by VSMCs apoptosis is a major factor leading to aortic wall thinning and aneurysm development. However, the molecular link between Klf5, Golph3l, and Golgi morphology alteration in the context of the aortic aneurysm is unclear. Here, we show that apoptosis-induced proliferation (AIP) in VSMCs occurs in AD and AAA tissues of humans and mice. The upregulation of Golph3l by Klf5 facilitates TNF-a and TNFSF12 secretion from AngII-stimulated VSMCs by inducing the compaction of the Golgi, which is essential for AIP and aneurysm development. Mechanistic studies reveal that 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, unveiling a novel lncRNA m6A modification-dependent regulatory mechanism of chromatin remodeling and transcription activation. Overall design: ApoE-/- mice, Tgln-cre mice, and Golph3l-flox mice containing loxP sites flanking exons 2 and 3 were purchased from Suzhou Cyagen Biotechnology Co., Ltd. Smooth muscle cell–specific Golph3l knockout (smcGolph3l-/- mice) by crossing Golph3l-flox mice and Tgln-cre mice (Golph3l-flox mice served as controls). Mice were kept under a 12-hour light/dark cycle at 23? with ad libitum access to food and water.