Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr -/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr -/- mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

中文翻译：

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长链非编码 RNA SNHG12 整合了 DNA-PK 介导的 DNA 损伤反应和血管衰老。

长链非编码 RNA (lncRNA) 是血管壁生物过程的新兴调节剂。然而，它们在动脉粥样硬化中的作用仍不清楚。我们使用 RNA 测序来分析在病变进展和消退阶段特别来自高胆固醇饮食的 Ldlr -/- 小鼠的主动脉内膜的 lncRNA。我们发现进化上保守的 lncRNA 小核仁宿主基因 12 (SNHG12) 在血管内皮中高度表达，并在病变进展过程中减少。SNHG12 敲低通过增加血管内皮中的 DNA 损伤和衰老，在 Ldlr -/- 小鼠中将动脉粥样硬化病变的形成加速了 2.4 倍，这与对脂质谱或血管壁炎症的影响无关。相反，SNHG12 的静脉内递送可保护内膜免受 DNA 损伤和动脉粥样硬化。LncRNA pulldown 结合液相色谱-串联质谱 (LC-MS/MS) 分析表明，SNHG12 与 DNA 依赖性蛋白激酶 (DNA-PK) 相互作用，DNA 损伤反应的重要调节因子。SNHG12 的缺失减少了 DNA-PK 与其结合伙伴 Ku70 和 Ku80 的相互作用，从而消除了 DNA 损伤修复。此外，抗 DNA 损伤剂烟酰胺核苷 (NR) 是一种临床级的 NAD+ 小分子激活剂，完全挽救了 SNHG12 敲低介导的损伤性 DNA 损伤、衰老和动脉粥样硬化的增加。猪和人类动脉粥样硬化标本中的 SNHG12 表达也降低，并且与 DNA 损伤和衰老标志物呈负相关。