Long noncoding RNA SNHG12 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 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.

• Authors: Stefan Haemmig, Dafeng Yang, Xinghui Sun, Debapria Das, Siavash Ghaffari, Roberto Molinaro, Lei Chen, Yihuan Deng, Dan Freeman, Norman Moullan, Yevgenia Tesmenitsky, A K M Khyrul Wara, Viorel Simion, Eugenia Shvartz, James F Lee, Tianlun Yang, Galina Sukova, Jarrod A Marto, Peter H Stone, Warren L Lee, Johan Auwerx, Peter Libby, Mark W Feinberg
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 531 (02 19 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32075942 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• RNA, Long Noncoding
• Protein Kinases
• DNA-Activated Protein Kinase

Topics

• Animals
• Cell Movement
• Cell Proliferation
• Chromatography, Liquid
• DNA Damage
• DNA-Activated Protein Kinase
• Endothelium, Vascular (pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Knockout
• Protein Kinases
• RNA, Long Noncoding (genetics)
• Swine
• Tandem Mass Spectrometry