Coptisine prevents angiotensin II‑induced endothelial cell injury and senescence via the lncRNA SNHG12/miR‑603/NAMPT pathway

Meng,Jing; Song,Xiaoying; Xing,Xinyue; Chen,Jingyi; Lou,Danfei

doi:10.3892/etm.2023.12356

Coptisine prevents angiotensin II‑induced endothelial cell injury and senescence via the lncRNA SNHG12/miR‑603/NAMPT pathway

Authors:
- Jing Meng
- Xiaoying Song
- Xinyue Xing
- Jingyi Chen
- Danfei Lou
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Affiliations: Emergency Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
Published online on: December 18, 2023 https://doi.org/10.3892/etm.2023.12356
Article Number: 68
Copyright: © Meng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Atherosclerosis (AS) is a major health problem and targeting the associated molecular pathways is critical for developing therapies. The present study investigated the effect of coptisine on human umbilical vein endothelial cells (HUVECs) in response to angiotensin II (Ang II) induction by focusing on cellular senescence, apoptosis and inflammation. HUVECs were treated with different Ang II concentrations and long non‑coding RNA small nucleolar RNA host gene 12 (SNHG12), microRNA (miRNA/miR)‑603 and nicotinamide phosphoribosyltransferase (NAMPT) expressions were assessed. Cell viability, nicotinamide adenine dinucleotide (NAD+) levels, senescence, apoptosis and inflammation were assessed. The interactions among SNHG12, miR‑603 and NAMPT were investigated using dual‑luciferase reporter gene assays and RNA pull‑down experiments. Coptisine treatment increased SNHG12 expression and attenuated Ang II‑induced adverse effects in HUVECs. SNHG12 silencing abrogated coptisine's protective effects, indicating that SNHG12 is a key mediator. SNHG12 targets miR‑603, which then directly targets NAMPT, an age‑related gene involved in NAD(+) regulation. Coptisine modulated the SNHG12/miR‑603/NAMPT pathway and miR‑603 inhibition enhanced the protective effects of coptisine. NAMPT overexpression reversed the negative effects of miR‑603 and enhanced the protective effect of the miR‑603 inhibitor. Finally, the protective mechanism of coptisine is linked to the regulation of NAD(+), sirtuin 3 (SIRT3) and p53. Coptisine treatment counteracted the AngII‑induced increase in SIRT3 and p53 protein levels, whereas the miR‑603 inhibitor potentiated the effect of coptisine. SNHG12 knockdown partially abolished these effects, which were reversed by NAMPT overexpression. In conclusion, the present study revealed a novel protective mechanism involving the SNHG12/miR‑603/NAMPT pathway in HUVECs exposed to Ang II, highlighting the potential therapeutic application of coptisine in treating atherosclerosis. These results suggested that coptisine exerts its protective effects by modulating the SNHG12/miR‑603/NAMPT axis, which ultimately affects the regulation of NAD(+), SIRT3 and p53. Future studies should explore the potential of the SNHG12/miR‑603/NAMPT pathway as a target for developing novel AS therapies.

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1	Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ and Han M: Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 7(131)2022.PubMed/NCBI View Article : Google Scholar
2	Libby P: The changing landscape of atherosclerosis. Nature. 592:524–533. 2021.PubMed/NCBI View Article : Google Scholar
3	Suzuki K, Susaki EA and Nagaoka I: Lipopolysaccharides and cellular senescence: Involvement in atherosclerosis. Int J Mol Sci. 23(11148)2022.PubMed/NCBI View Article : Google Scholar
4	You Y, Sun X, Xiao J, Chen Y, Chen X, Pang J, Mi J, Tang Y, Liu Q and Ling W: Inhibition of S-adenosylhomocysteine hydrolase induces endothelial senescence via hTERT downregulation. Atherosclerosis. 353:1–10. 2022.PubMed/NCBI View Article : Google Scholar
5	Chen L, Qu H, Guo M, Zhang Y, Cui Y, Yang Q, Bai R and Shi D: ANRIL and atherosclerosis. J Clin Pharm Ther. 45:240–248. 2020.PubMed/NCBI View Article : Google Scholar
6	Liu Y, Gong S, Li K, Wu G, Zheng X, Zheng J, Lu X, Zhang L, Li J, Su Z, et al: Coptisine protects against hyperuricemic nephropathy through alleviating inflammation, oxidative stress and mitochondrial apoptosis via PI3K/Akt signaling pathway. Biomed Pharmacother. 156(113941)2022.PubMed/NCBI View Article : Google Scholar
7	Kim SY, Hwangbo H, Kim MY, Ji SY, Lee H, Kim GY, Kwon CY, Leem SH, Hong SH, Cheong J and Choi YH: Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Arch Biochem Biophys. 697(108688)2021.PubMed/NCBI View Article : Google Scholar
8	Suzuki H, Tanabe H, Mizukami H and Inoue M: Differential gene expression in rat vascular smooth muscle cells following treatment with coptisine exerts a selective antiproliferative effect. J Nat Prod. 74:634–638. 2011.PubMed/NCBI View Article : Google Scholar
9	Suzuki H, Tanabe H, Mizukami H and Inoue M: Selective regulation of multidrug resistance protein in vascular smooth muscle cells by the isoquinoline alkaloid coptisine. Biol Pharm Bull. 33:677–682. 2010.PubMed/NCBI View Article : Google Scholar
10	Xu Z, Feng W, Shen Q, Yu N, Yu K, Wang S, Chen Z, Shioda S and Guo Y: Rhizoma coptidis and berberine as a natural drug to combat aging and aging-related diseases via anti-oxidation and AMPK activation. Aging Dis. 8:760–777. 2017.PubMed/NCBI View Article : Google Scholar
11	Cao Q, Wu J, Wang X and Song C: Noncoding RNAs in vascular aging. Oxid Med Cell Longev. 2020(7914957)2020.PubMed/NCBI View Article : Google Scholar
12	Yu XH, Deng WY, Chen JJ, Xu XD, Liu XX, Chen L, Shi MW, Liu QX, Tao M and Ren K: LncRNA kcnq1ot1 promotes lipid accumulation and accelerates atherosclerosis via functioning as a ceRNA through the miR-452-3p/HDAC3/ABCA1 axis. Cell Death Dis. 11(1043)2020.PubMed/NCBI View Article : Google Scholar
13	Haemmig S, Yang D, Sun X, Das D, Ghaffari S, Molinaro R, Chen L, Deng Y, Freeman D, Moullan N, et al: Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence. Sci Transl Med. 12(eaaw1868)2020.PubMed/NCBI View Article : Google Scholar
14	Ramakrishnan V, Xu B, Akers J, Nguyen T, Ma J, Dhawan S, Ning J, Mao Y, Hua W, Kokkoli E, et al: Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas. EBioMedicine. 55(102736)2020.PubMed/NCBI View Article : Google Scholar
15	Lu J, Wang L, Chen W, Wang Y, Zhen S, Chen H, Cheng J, Zhou Y, Li X and Zhao L: miR-603 targeted hexokinase-2 to inhibit the malignancy of ovarian cancer cells. Arch Biochem Biophys. 661:1–9. 2019.PubMed/NCBI View Article : Google Scholar
16	Garten A, Schuster S, Penke M, Gorski T, de Giorgis T and Kiess W: Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol. 11:535–546. 2015.PubMed/NCBI View Article : Google Scholar
17	Abdellatif M, Sedej S and Kroemer G: NAD⁺ metabolism in cardiac health, aging, and disease. Circulation. 144:1795–1817. 2021.PubMed/NCBI View Article : Google Scholar
18	Cao M, Zhao Q, Sun X, Qian H, Lyu S, Chen R, Xia H and Yuan W: Sirtuin 3: Emerging therapeutic target for cardiovascular diseases. Free Radic Biol Med. 180:63–74. 2022.PubMed/NCBI View Article : Google Scholar
19	Yuan L, Yang J, Li Y, Yuan L, Liu F, Yuan Y and Tang X: Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway. J Cell Mol Med. 26:3702–3715. 2022.PubMed/NCBI View Article : Google Scholar
20	Xu S, Li L, Wu J, An S, Fang H, Han Y, Huang Q, Chen Z and Zeng Z: Melatonin attenuates sepsis-induced small-intestine injury by upregulating SIRT3-mediated oxidative-stress inhibition, mitochondrial protection, and autophagy induction. Front Immunol. 12(625627)2021.PubMed/NCBI View Article : Google Scholar
21	Zhang Q, Liu XM, Hu Q, Liu ZR, Liu ZY, Zhang HG, Huang YL, Chen QH, Wang WX and Zhang XK: Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway. J Transl Med. 19(463)2021.PubMed/NCBI View Article : Google Scholar
22	Barjaktarovic Z, Kempf SJ, Sriharshan A, Merl-Pham J, Atkinson MJ and Tapio S: Ionizing radiation induces immediate protein acetylation changes in human cardiac microvascular endothelial cells. J Radiat Res. 56:623–632. 2015.PubMed/NCBI View Article : Google Scholar
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
24	Navas LE and Carnero A: NAD⁺ metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther. 6(2)2021.PubMed/NCBI View Article : Google Scholar
25	O'Donoghue ML, Giugliano RP, Wiviott SD, Atar D, Keech A, Kuder JF, Im K, Murphy SA, Flores-Arredondo JH, López JAG, et al: Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. Circulation. 146:1109–1119. 2022.PubMed/NCBI View Article : Google Scholar
26	Bytyçi I, Penson PE, Mikhailidis DP, Wong ND, Hernandez AV, Sahebkar A, Thompson PD, Mazidi M, Rysz J, Pella D, et al: Prevalence of statin intolerance: A meta-analysis. Eur Heart J. 43:3213–3223. 2022.PubMed/NCBI View Article : Google Scholar
27	Zhang X, Qin Y, Ruan W, Wan X, Lv C, He L, Lu L and Guo X: Targeting inflammation-associated AMPK//Mfn-2/MAPKs signaling pathways by baicalein exerts anti-atherosclerotic action. Phytother Res. 35:4442–4455. 2021.PubMed/NCBI View Article : Google Scholar
28	Dörffel Y, Franz S, Pruss A, Neumann G, Rohde W, Burmester GR and Scholze J: Preactivated monocytes from hypertensive patients as a factor for atherosclerosis? Atherosclerosis. 157:151–160. 2001.PubMed/NCBI View Article : Google Scholar
29	Liu B, Piao X, Niu W, Zhang Q, Ma C, Wu T, Gu Q, Cui T and Li S: Kuijieyuan decoction improved intestinal barrier injury of ulcerative colitis by affecting TLR4-dependent PI3K/AKT/NF-κB oxidative and inflammatory signaling and gut microbiota. Front Pharmacol. 11(1036)2020.PubMed/NCBI View Article : Google Scholar
30	Yang HG, Wang TP, Hu SA, Hu CZ, Jiang CH and He Q: Long non-coding RNA SNHG12, a new therapeutic target, regulates miR-199a-5p/Klotho to promote the growth and metastasis of intrahepatic cholangiocarcinoma cells. Front Med (Lausanne). 8(680378)2021.PubMed/NCBI View Article : Google Scholar
31	Qian W, Zheng ZQ, Nie JG, Liu LJ, Meng XZ, Sun H, Xiao FM and Kang T: LncRNA SNHG12 alleviates hypertensive vascular endothelial injury through miR-25-3p/SIRT6 pathway. J Leukoc Biol. 110:651–661. 2021.PubMed/NCBI View Article : Google Scholar
32	Covarrubias AJ, Perrone R, Grozio A and Verdin E: NAD⁺ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 22:119–141. 2021.PubMed/NCBI View Article : Google Scholar
33	Yang L, Shen J, Liu C, Kuang Z, Tang Y, Qian Z, Guan M, Yang Y, Zhan Y, Li N and Li X: Nicotine rebalances NAD⁺ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity. Nat Commun. 14(900)2023.PubMed/NCBI View Article : Google Scholar
34	Gong H, Chen H, Xiao P, Huang N, Han X, Zhang J, Yang Y, Li T, Zhao T, Tai H, et al: miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD⁺/SIRT inactivation. Signal Transduct Target Ther. 7(66)2022.PubMed/NCBI View Article : Google Scholar
35	Diao Z, Ji Q, Wu Z, Zhang W, Cai Y, Wang Z, Hu J, Liu Z, Wang Q, Bi S, et al: SIRT3 consolidates heterochromatin and counteracts senescence. Nucleic Acids Res. 49:4203–4219. 2021.PubMed/NCBI View Article : Google Scholar
36	Nahálková J: Focus on molecular functions of anti-aging deacetylase SIRT3. Biochemistry (Mosc). 87:21–34. 2022.PubMed/NCBI View Article : Google Scholar
37	Yan P, Li Z, Xiong J, Geng Z, Wei W, Zhang Y, Wu G, Zhuang T, Tian X, Liu Z, et al: LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity. Cell Rep. 37(110038)2021.PubMed/NCBI View Article : Google Scholar
38	Guo RW, Yang LX, Li MQ, Liu B and Wang XM: Angiotensin II induces NF-kappa B activation in HUVEC via the p38MAPK pathway. Peptides. 27:3269–3275. 2006.PubMed/NCBI View Article : Google Scholar