NEAT1 regulates VSMC differentiation and calcification in as long noncoding RNA NEAT1 enhances phenotypic and osteogenic switching of vascular smooth muscle cells in atherosclerosis via scaffolding EZH2.

Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901225 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1563 (Electronic) Linking ISSN: 03636143 NLM ISO Abbreviation: Am J Physiol Cell Physiol Subsets: MEDLINE

Original Publication: Bethesda, Md. : American Physiological Society,

RNA, Long Noncoding*/genetics ; RNA, Long Noncoding*/metabolism ; Enhancer of Zeste Homolog 2 Protein*/metabolism ; Enhancer of Zeste Homolog 2 Protein*/genetics ; Muscle, Smooth, Vascular*/metabolism ; Muscle, Smooth, Vascular*/pathology ; Osteogenesis*/genetics ; Atherosclerosis*/genetics ; Atherosclerosis*/pathology ; Atherosclerosis*/metabolism ; Myocytes, Smooth Muscle*/metabolism ; Myocytes, Smooth Muscle*/pathology ; Cell Differentiation* ; Vascular Calcification*/pathology ; Vascular Calcification*/genetics ; Vascular Calcification*/metabolism; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Cell Proliferation ; Phenotype ; Cells, Cultured ; Humans ; Cell Movement

Atherosclerosis (AS) is a significant contributor to cardio-cerebrovascular ischemia diseases, resulting in high mortality rates worldwide. During AS, vascular smooth muscle cells (VSMCs) play a crucial role in plaque formation by undergoing phenotypic and osteogenic switching. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has previously been identified as a nuclear regulator that promotes tumorigenesis and metastasis, but its role in regulating VSMCs in AS remains unclear. Our study aimed to investigate the biological functions and specific mechanisms of NEAT1 in regulating VSMCs in AS. We found that NEAT1 was upregulated in the aortas of AS mouse models and dedifferentiated primary VSMCs. Silencing NEAT1 in vitro attenuated the proliferation, migration, and osteogenic differentiation of VSMCs, while NEAT1 overexpression had the opposite effect. Furthermore, NEAT1 promoted VSMC osteogenic differentiation and vascular calcification in both in vivo and in vitro vascular calcification models. We also discovered that NEAT1 directly activates enhancer of zeste homolog 2 (EZH2), an epigenetic enzyme that suppresses the expression of senescence- and antimigration-related genes, by translocating it into the nucleus. CUT&Tag assay revealed that NEAT1 guides EZH2 to the promoters of senescence-related genes (P16, P21, and TIMP3), methylating local histones to reduce their transcription. Our findings suggest that NEAT1 functions in AS by modulating the epigenetic function of EZH2, which enhances the proliferation, migration, and osteogenic differentiation of VSMCs. This study provides new insights into the molecular mechanisms underlying the pathogenesis of AS and highlights the potential of NEAT1 as a therapeutic target of AS. NEW & NOTEWORTHY Our study demonstrates that the upregulation of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes proliferation and migration during phenotypic switching of vascular smooth muscle cells in atherosclerosis. We also provide in vivo and in vitro evidence that NEAT1 accelerates vascular calcification. Our findings identified the direct interaction between enhancer of zeste homolog 2 (EZH2) and NEAT1 during atherosclerosis. NEAT1 is necessary for EZH2 to translocate from the cytoplasm to the nucleus, where EZH2 epigenetically inhibits the expression of genes related to senescence and antimigration.

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82070249 MOST | National Natural Science Foundation of China (NSFC); 82200453 MOST | National Natural Science Foundation of China (NSFC)

Keywords: NEAT1; VSMC phenotypic switching; atherosclerosis; epigenetic regulation; vascular calcification

0 (RNA, Long Noncoding)
EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
0 (NEAT1 long non-coding RNA, mouse)
EC 2.1.1.43 (Ezh2 protein, mouse)
0 (NEAT1 long non-coding RNA, human)
EC 2.1.1.43 (EZH2 protein, human)

Date Created: 20240422 Date Completed: 20240606 Latest Revision: 20240905

20240905

PMC11371316

10.1152/ajpcell.00587.2023

38646788