Novel role of the lncRNA NEAT1 in smooth muscle phenotypic modulation

The overall goal of the proposed research is to determine the previously unrecognized role of the (long non-coding RNA) lncRNA NEAT1 (nuclear paraspeckle assembly transcript 1) and its novel underlying mechanism in regulating the phenotypic switching of vascular smooth muscle cells (VSMCs). Many vascular diseases in humans, such as intimal hyperplasia post-angioplasty, are largely dependent upon VSMC phenotypic switching from a contractile to a 'synthetic' phenotype that is associated with reduced smooth muscle-specific gene expression and increased cell proliferation and migration. Therefore, unraveling the mechanisms for the VSMC phenotypic switching is crucial for understanding the pathology of VSMC related vascular diseases and ultimately designing therapeutic agents for treatment. Emerging evidences demonstrate that lncRNAs represent a novel class of regulators for gene expression. In an effort to search for the lncRNAs potentially being involved in the vascular injury, we conducted a large-scale lncRNA array screen using the rat carotid artery injured by a balloon denudation, a procedure resembles resembling angioplasty in humans. From thisThis screen we discoveredrevealed that the lncRNA NEAT1 is induced in response to the arterial injury in vivo. Furthermore, expression of NEAT1 is also induced in the lesion of apoE knockout mouse of atherosclerotic model. Loss- and gain-of-function NEAT1 revealed that NEAT1 not only increases proliferation, migration and inflammation of VSMCs but also decreases expression of smooth muscle-specific contractile proteins. Therefore, experiments described in this proposal will test the hypothesis that, the induction of the lncRNA NEAT1 in vascular disease states iss critical for the development of a pro-inflammatory smooth muscle phenotype phenotypic modulation . In Aim 1, we will determine the role of NEAT1 in the progression of atherosclerosis using NEAT1/apoE double knock-out mice compared to apoE knockout mice alone after high fat diet feeding. In Aim 2, we will determine the mechanism by which NEAT1 induces inflammatory chemokine gene expression. Completion of proposed studies will provide novel insights into the integrative mechanisms underlying smooth muscle phenotypic modulation, open up new avenues of research on lncRNAs in VSMCs and will reveal the potential of targeting NEAT1 as a therapy to help prevent or treat many vascular diseases. (AHA Program: Established Investigator Award)