LncRNA DANCR Promotes Macrophage Lipid Accumulation Through Modulation of Membrane Cholesterol Transporters

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2024 Jul 5

PMID 38968577

Authors

Guo-Jun Zhao

Yu Wang

Jun-Hong An

Wan-Ying Tang

Xiao-Dan Xu

Kun Ren

Affiliations

Soon will be listed here.

Abstract

The progression of atherosclerosis (AS), the pathological foundation of coronary artery disease (CAD), is featured by massive lipid deposition in the vessel wall. LncRNAs are implicated in lipid disorder and AS, whereas the specific role of lncRNA DANCR in atherogenesis remains unknown. Here, we demonstrated that DANCR promotes macrophage lipid accumulation by regulating the expression of membrane cholesterol transport proteins. qPCR showed that compared to control groups, CAD patients and atherosclerotic mice had higher DANCR levels. Treating human THP-1 macrophages and mouse RAW264.7 macrophages with ox-LDL significantly upregulated the expression levels of DANCR. Oil Red O staining showed that the silence of DANCR robustly reduced, while overexpression of DANCR significantly increased the numbers and size of lipid droplets in ox-LDL-treated THP-1 macrophages. In contrast, the opposite phenomena were observed in DANCR overexpressing cells. The expression of ABCA1, ABCG1, SR-BI, and NBD-cholesterol efflux was increased obviously by DANCR inhibition and decreased by DANCR overexpression, respectively. Furthermore, transfection with DANCR siRNA induced a robust decrease in the levels of CD36, SR-A, and Dil-ox-LDL uptake, while DANCR overexpression amplified the expression of CD36, SR-A and the uptake of Dil-ox-LDL in lipid-laden macrophages. Lastly, we found that the effects of DANCR on macrophage lipid accumulation and the expression of membrane cholesterol transport proteins were not likely related to miR-33a. The present study unraveled the adverse role of DANCR in foam cell formation and its relationship with cholesterol transport proteins. However, the competing endogenous RNA network underlying these phenomena warrants further exploration.

References

Ouimet M, Ediriweera H, Afonso M, Ramkhelawon B, Singaravelu R, Liao X . microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2017; 37(6):1058-1067. PMC: 5494696. DOI: 10.1161/ATVBAHA.116.308916. View

Lin C, Lin F, Ho L, Tsai C, Cheng S, Wu W . PKCδ signalling regulates SR-A and CD36 expression and foam cell formation. Cardiovasc Res. 2012; 95(3):346-55. DOI: 10.1093/cvr/cvs189. View

Zhao Z, de Beer M, Cai L, Asmis R, de Beer F, de Villiers W . Low-density lipoprotein from apolipoprotein E-deficient mice induces macrophage lipid accumulation in a CD36 and scavenger receptor class A-dependent manner. Arterioscler Thromb Vasc Biol. 2004; 25(1):168-73. DOI: 10.1161/01.ATV.0000149145.00865.d9. View

Pei C, Fei K, Yuan X, Gong X . LncRNA DANCR aggravates the progression of ovarian cancer by downregulating UPF1. Eur Rev Med Pharmacol Sci. 2019; 23(24):10657-10663. DOI: 10.26355/eurrev_201912_19763. View

Rader D, Hovingh G . HDL and cardiovascular disease. Lancet. 2014; 384(9943):618-625. DOI: 10.1016/S0140-6736(14)61217-4. View

Pi S, Mao L, Chen J, Shi H, Liu Y, Guo X . The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy. 2020; 17(4):980-1000. PMC: 8078663. DOI: 10.1080/15548627.2020.1741202. View

Zhang M, Tang M, Wu Q, Wang Z, Chen Z, Ding H . LncRNA DANCR attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through regulating of miR-33a-5p/XBP1s. Aging (Albany NY). 2020; 12(2):1778-1791. PMC: 7053632. DOI: 10.18632/aging.102712. View

Hu J, Luo T, Xi D, Guo K, Hu L, Zhao J . Silencing ZAP70 prevents HSP65-induced reverse cholesterol transport and NF-κB activation in T cells. Biomed Pharmacother. 2018; 102:271-277. DOI: 10.1016/j.biopha.2018.03.082. View

Wang J, Zhou J, Zheng Q, Gan H, Wang H . Dialysis method alters the expression of microRNA-33a and its target genes ABCA1, ABCG1 in THP-1 macrophages. Ther Apher Dial. 2014; 18(1):44-50. DOI: 10.1111/1744-9987.12040. View

10.

Aiello R, Brees D, Bourassa P, Royer L, Lindsey S, Coskran T . Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol. 2002; 22(4):630-7. DOI: 10.1161/01.atv.0000014804.35824.da. View

11.

Wang B, Tang X, Yao L, Wang Y, Chen Z, Li M . Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis. J Clin Invest. 2022; 132(10). PMC: 9106359. DOI: 10.1172/JCI154217. View

12.

Hu X, Ma R, Fu W, Zhang C, Du X . LncRNA UCA1 sponges miR-206 to exacerbate oxidative stress and apoptosis induced by ox-LDL in human macrophages. J Cell Physiol. 2019; 234(8):14154-14160. DOI: 10.1002/jcp.28109. View

13.

Jiang N, Wang X, Xie X, Liao Y, Liu N, Liu J . lncRNA DANCR promotes tumor progression and cancer stemness features in osteosarcoma by upregulating AXL via miR-33a-5p inhibition. Cancer Lett. 2017; 405:46-55. DOI: 10.1016/j.canlet.2017.06.009. View

14.

Yu X, Zhang D, Zheng X, Tang C . Cholesterol transport system: An integrated cholesterol transport model involved in atherosclerosis. Prog Lipid Res. 2018; 73:65-91. DOI: 10.1016/j.plipres.2018.12.002. View

15.

Li Y, Shen S, Ding S, Wang L . LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. J Cell Biochem. 2017; 119(2):1911-1921. DOI: 10.1002/jcb.26352. View

16.

Zhang Y, Xu X, Ma J, Liu Y, Duan C, Liu Y . Loss of CD226 protects apolipoprotein E-deficient mice from diet-induced atherosclerosis. Biochim Biophys Acta Mol Basis Dis. 2022; 1868(9):166452. DOI: 10.1016/j.bbadis.2022.166452. View

17.

Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M . MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J Am Heart Assoc. 2013; 1(6):e003376. PMC: 3540673. DOI: 10.1161/JAHA.112.003376. View

18.

Singh S, Changkija S, Mudgal R, Ravichandiran V . Bioactive components to inhibit foam cell formation in atherosclerosis. Mol Biol Rep. 2022; 49(3):2487-2501. DOI: 10.1007/s11033-021-07039-9. View

19.

Vaidya M, Jentsch J, Peters S, Keul P, Weske S, Graler M . Regulation of ABCA1-mediated cholesterol efflux by sphingosine-1-phosphate signaling in macrophages. J Lipid Res. 2019; 60(3):506-515. PMC: 6399502. DOI: 10.1194/jlr.M088443. View

20.

Mao M, Lei H, Liu Q, Chen Y, Zhao L, Li Q . Effects of miR-33a-5P on ABCA1/G1-mediated cholesterol efflux under inflammatory stress in THP-1 macrophages. PLoS One. 2014; 9(10):e109722. PMC: 4201478. DOI: 10.1371/journal.pone.0109722. View