LncRNA SNHG12, vascular senescence, and atherosclerosis

LncRNA SNHG12、血管衰老和动脉粥样硬化

• 批准号: 9973625
• 负责人: MARK W FEINBERG
• 金额: $ 64.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973625
• 关键词: Arterial Fatty Streak; Atherosclerosis; Attention; Bioinformatics; Biological Assay; Biological Process; Biology; Biophysics; Blood Vessels; Cause of Death; Cell Adhesion Molecules; Cell Aging; Characteristics; Chromatin Remodeling Factor; Chronic; Chronic Disease; Code; DNA Damage; DNA Markers; DNA-dependent protein kinase; Deletion Mutation; Disease; Disease Progression; Endothelial Cells; Endothelium; Family suidae; Foundations; Functional disorder; Gamma-H2AX; Genes; Goals; Human; Hyperlipidemia; Immunoprecipitation; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lesion; Leukocytes; Link; Lipids; Low-Density Lipoproteins; Mass Spectrum Analysis; Mediating; Molecular; Mus; Myocardial Infarction; Pathway interactions; Peripheral Vascular Diseases; Permeability; Phase; Play; Process; Proteins; RNA; Regulation; Reporter Genes; Repression; Research; Risk Factors; Rodent; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Small Nucleolar RNA; Stimulus; Stroke; TP53 gene; Therapeutic; Transgenic Mice; Untranslated RNA; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelium; atherogenesis; base; cell type; chemokine; cytokine; frontier; in vivo; insight; molecular imaging; multidisciplinary; nanomedicine; nanoparticle; nicotinamide-beta-riboside; novel; novel therapeutic intervention; recruit; response; senescence; transcriptome sequencing; transcytosis

Long non-coding RNAs (lncRNAs) have garnered widespread attention as emerging regulators of diverse biological processes relevant to atherosclerosis. However, the identity and roles of specific lncRNAs within atherosclerotic lesions are not well defined. Using RNA-Seq profiling to identify lncRNAs derived specifically from the aortic intima of LDLR-/- mice during lesion progression and regression phases, we identify the lncRNA Small Nucleolar Host Gene-12 (SNHG12). SNHG12 is highly enriched in the vascular endothelium across mice, pigs, and humans and is significantly reduced with atherosclerotic lesion progression, but increased with regression. Our preliminary studies show that gapmeR-mediated silencing of SNHG12 potently accelerated atherosclerotic lesion formation by over 2-fold in LDLR-/- mice. Remarkably, the increased lesional effects were not driven by lipid-lowering or by inflammatory recruitment of lesional leukocytes, but rather by increased DNA damage (γH2AX) and senescence (p16, p21, p27) in the vascular endothelium. Accumulating studies demonstrate that vascular senescence induced by the DNA damage response (DDR) may adversely contribute to chronic inflammation in atherosclerotic lesions. However, the mechanisms linking senescence and atherosclerotic lesion formation remain poorly understood. LncRNAs play important regulatory roles by interacting with RNA, chromatin modifiers, or protein- coding genes. Mechanistically, using a modified RNA IP (RIP)-mass spectrometry pulldown assay, we identify that SNHG12 interacts with the DNA-dependent protein kinase (DNA-PK) to control the DNA-damage response. Preliminary studies show SNHG12 deficiency in ECs significantly increased DNA damage, markers of senescence, and EC permeability to LDL. Moreover, we demonstrate that the NAD+ precursor nicotinamide riboside (NR), that suppresses endothelial senescence, may function in an SNHG12-dependent manner. These observations provide the foundation for the central hypothesis that endothelial SNHG12 deficiency, via regulatory effects on DNA-PK and the DNA damage response, promotes vascular senescence, senescence- associated inflammation, and atherosclerosis. To elucidate this further, three aims are proposed. In Aim1, we will delineate the molecular basis for SNHG12's ability to regulate DNA-PK-mediated DNA damage response and vascular senescence in ECs. In Aim2, we will determine the effect of altering lncRNA SNHG12 expression in an EC-specific manner on the DNA damage response and atherosclerotic progression and regression. In Aim3, we will explore the molecular mechanisms by which stimuli repress and NR rescues SNHG12 expression in ECs, and we will determine whether the anti-senescent effects of NR are SNHG12-dependent. This multi-disciplinary team in the fields of non-coding RNA biology, molecular imaging, nanomedicine, bioinformatics, and atherosclerosis research will establish an unprecedented molecular view of this lncRNA in lesions that can inform a new frontier in the regulation of vascular senescence and atherosclerosis.

长链非编码rna （Long non-coding rna, lncRNAs）作为一种新兴的调控因子受到了广泛的关注