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

Area of Science:

• Vascular Biology
• RNA Biology
• Molecular Medicine

Background:

• Vascular smooth muscle cell (VSMC) inflammation is a critical early event in vascular disease pathogenesis.
• The role of human-specific long noncoding RNAs (lncRNAs) in regulating VSMC inflammation remains largely unexplored.

Purpose of the Study:

• To identify and characterize novel human-specific lncRNAs involved in VSMC inflammation.
• To elucidate the molecular mechanisms by which these lncRNAs regulate VSMC inflammatory responses and contribute to vascular disease.

Main Methods:

• Bulk RNA sequencing of human VSMCs identified a novel lncRNA, INKILN.
• INKILN expression was analyzed in various VSMC models and human vascular tissues.
• Luciferase reporter assays, ChIP, and interaction studies (RNA-protein, protein-protein) investigated INKILN's transcriptional regulation and function.
• Loss-of-function and gain-of-function studies, alongside transgenic mouse models, assessed INKILN's role in VSMC inflammation and neointimal formation.

Main Results:

• INKILN expression is decreased in contractile VSMCs but upregulated in human atherosclerosis and abdominal aortic aneurysm.
• INKILN transcriptionally activates proinflammatory genes via the p65/NF-κB pathway and stabilizes MKL1.
• INKILN depletion inhibits IL-1β-induced nuclear translocation of p65 and MKL1, disrupting their interaction and enhancing MKL1 ubiquitination by USP10.
• INKILN promotes neointimal formation in a mouse model of vascular injury.

Conclusions:

• INKILN acts as a key regulator of VSMC inflammation through an INKILN/MKL1/USP10 axis.
• Human bacterial artificial chromosome transgenic mice provide a relevant model for studying human-specific lncRNAs in vascular disease.