Long noncoding RNA <i>SNHG12</i> integrates a DNA-PK–mediated DNA damage response and vascular senescence

Abstract

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 <i>Ldlr</i> ^-/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (<i>SNHG12</i>) is highly expressed in the vascular endothelium and decreases during lesion progression. <i>SNHG12</i> knockdown accelerated atherosclerotic lesion formation by 2.4-fold in <i>Ldlr</i> ^-/- 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 <i>SNHG12</i> 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 <i>SNHG12</i> interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of <i>SNHG12</i> 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 <i>SNHG12</i> knockdown. <i>SNHG12</i> 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.