Abstract
Background: Long non-coding RNAs (lncRNAs) recently have been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results: The downstream targets of p53 also been detected by un-bias mRNA array and specific qPCR. Furthermore, bioinformatics prediction, RNA-Immunoprecipitation, biotin-labeled RNA-pulldown and deletion mapping were performed to test the potential interaction between lincRNA-p21 and MDM2. Co-IP, genome-wide ChIP-seq and ChIP-qPCR were preformed to verify the possible influence on p53 transcriptional activity. We further investigated the function of lincRNA-p21 in vivo, therefore recombinant lincRNA-p21 knockdown lentivirus were injected into the injured area of carotid arteries injury mouse model. Then the expression of lincRNA-p21 in vascular samples of clinical coronary disease patients were also detected. We identified lincRNA-p21 as a key regulator of atherosclerosis. Expression of lincRNA-p21 was dramatically down-regulated in atherosclerotic plaques of ApoE-/- mice, an animal model for AS. Through loss- and gain-of function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in VSMCs in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Mechanistically, we revealed that lincRNA-p21, which is a transcriptional target of p53, feeds back to enhance p53 transcriptional activity via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 to regulate apoptosis, cell proliferation and suppress neointima formation. Conclusions: Our studies identified lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis.
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