INKILN is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10

作者：Wei Zhang, Jinjing Zhao, Lin Deng, Nestor Ishimwe, Jessica Pauli, Wen Wu, Shengshuai Shan, W. Kempf, Margaret D. Ballantyne, David Kim, Qing Lyu, Matthew Bennett, Julie Rodor, Adam W. Turner, Yao Wei Lu, Ping Gao, Mihyun Choi, Ganesh Warthi, Ha Won Kim, Margarida Barroso, William B. Bryant, Clint L. Miller, Neal L. Weintraub, Lars Mäegdefessel, Joseph M. Miano, Andrew H. Baker, Xiaochun Long · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.123.063760 · 被引用次数：65 · 研究领域：Cancer-related molecular mechanisms research、RNA modifications and cancer、Circular RNAs in diseases

Background: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. Methods: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA–protein and protein–protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury–induced neointimal formation. Results: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key a...