PCSK9 mediates the oxidative low‑density lipoprotein‑induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway

Zeng,Junfa; Tao,Jun; Xi,Linzhen; Wang,Zuo; Liu,Lushan

doi:10.3892/ijmm.2021.4886

PCSK9 mediates the oxidative low‑density lipoprotein‑induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway

Authors:
- Junfa Zeng
- Jun Tao
- Linzhen Xi
- Zuo Wang
- Lushan Liu
View Affiliations

Affiliations: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: February 11, 2021 https://doi.org/10.3892/ijmm.2021.4886
Article Number: 53
Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to explore the role and mechanisms of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the oxidized low‑density lipoprotein (oxLDL)‑induced pyroptosis of vascular endothelial cells. For this purpose, human umbilical vein endothelial cells (HUVECs) were incubated with oxLDL (100 µg/ml) for 24 h to induce pyroptosis, which was detected using PI/hoechst33342 double staining. The expression of pyroptosis‑associated molecules was measured by western blot analysis and RT‑qPCR. Reactive oxygen species (ROS) and membrane potential were examined through ROS probe and JC‑1 staining, respectively. PCSK9 and mitochondrial ubiquinol‑cytochrome c reductase core protein 1 (UQCRC1) protein were knocked down by small interfering RNA (siRNA). PCSK9 was overexpressed by lentivirus. The results revealed that oxLDL induced HUVEC injury, pyroptosis and inflammatory factor release, and upregulated the expression of PCSK9 protein in the HUVECs in a concentration‑dependent manner. The silencing of PCSK9 expression with siRNA suppressed the oxLDL‑induced damage to HUVECs, the release of inflammatory substances and the occurrence of pyroptosis. In addition, oxLDL inhibited UQCRC1 expression, promoted mitochondrial membrane potential collapse and damaged mitochondrial function; however, these processes were reversed by the silencing of PCSK9. PCSK9 overexpression induced the pyroptosis of HUVECs, the generation of ROS and the disorder of mitochondrial function by inhibiting UQCRC1. Therefore, PCSK9 mediates the oxLDL‑induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway.

View Figures

View References

1	Moss JW and Ramji DP: Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets. Future Med Chem. 8:1317–1330. 2016. View Article : Google Scholar : PubMed/NCBI
2	Libby P, Ridker PM and Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature. 473:317–325. 2011. View Article : Google Scholar : PubMed/NCBI
3	Glass CK and Witztum JL: Atherosclerosis. Cell. 104:503–516. 2001. View Article : Google Scholar : PubMed/NCBI
4	Horton JD, Cohen JC and Hobbs HH: Molecular biology of PCSK9: Its role in LDL metabolism. Trends Biochem Sci. 32:71–77. 2007. View Article : Google Scholar : PubMed/NCBI
5	Hedrick JA: Targeting PCSK9 for the treatment of hypercholesterolemia. Curr Opin Invest Drugs. 10:938–946. 2009.
6	Xu YJ, Zheng L, Hu YW and Wang Q: Pyroptosis and its relationship to atherosclerosis. Clin Chim Acta. 476:28–37. 2018. View Article : Google Scholar
7	Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A and Mirzaei H: NLRP3 inflammasome: Its regulation and involvement in atherosclerosis. J Cell Physiol. 233:2116–2132. 2018. View Article : Google Scholar
8	Shah PK and Lecis D: Inflammation in atherosclerotic cardiovascular disease. F1000Res. 8:F10002019. View Article : Google Scholar : PubMed/NCBI
9	Zhaolin Z, Jiaojiao C, Peng W, Yami L, Tingting Z, Jun T, Shiyuan W, Jinyan X, Dangheng W, Zhisheng J and Zuo W: OxLDL induces vascular endothelial cell pyroptosis through miR-125a-5p/TET2 pathway. J Cell Physiol. 234:7475–7491. 2019.
10	Mottis A, Herzig S and Auwerx J: Mitocellular communication: Shaping health and disease. Science. 366:827–832. 2019. View Article : Google Scholar : PubMed/NCBI
11	Ding Z, Liu S, Wang X, Deng X, Fan Y, Sun C, Wang Y and Mehta JL: Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal. 22:760–771. 2015. View Article : Google Scholar :
12	Bao HL, Liao FJ, Fang L, Zhong F, Liu W and Li JQ: Effect and mechanism of PCSK9 on lectin-like oxidized low-density lipoprotein receptor-1 mediated oxidized low-density lipoprotein uptake by THP-1 derived macrophages. Zhonghua Xin Xue Guan Bing Za Zhi. 47:367–373. 2019.In Chinese. PubMed/NCBI
13	Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS and Liu LS: PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via bcl/Bax-caspase9-caspase3 pathway. Mol Cell Biochem. 359:347–358. 2012. View Article : Google Scholar
14	Chen JJ, Tao J, Zhang XL, Xia LZ, Zeng JF, Zhang H, Wei DH, Lv YC, Li GH and Wang Z: Inhibition of the ox-LDL-induced pyroptosis by FGF21 of human umbilical vein endothelial cells through the TET2-UQCRC1-ROS pathway. DNA Cell Biol. 39:661–670. 2020. View Article : Google Scholar : PubMed/NCBI
15	Davies PF: Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med. 6:16–26. 2009. View Article : Google Scholar
16	Zhang L, Yuan M, Zhang L, Wu B and Sun X: Adiponectin alleviates NLRP3-inflammasome-mediated pyroptosis of aortic endothelial cells by inhibiting FoxO4 in arteriosclerosis. Biochem Biophys Res Commun. 514:266–272. 2019. View Article : Google Scholar : PubMed/NCBI
17	Chang W, Lin J, Dong J and Li D: Pyroptosis: An inflammatory cell death implicates in atherosclerosis. Med Hypotheses. 81:484–486. 2013. View Article : Google Scholar : PubMed/NCBI
18	Zhou R, Yazdi AS, Menu P and Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–225. 2011. View Article : Google Scholar
19	Lin XL, Xiao LL, Tang ZH, Jiang ZS and Liu MH: Role of PCSK9 in lipid metabolism and atherosclerosis. Biomed Pharmacother. 104:36–44. 2018. View Article : Google Scholar : PubMed/NCBI
20	Vozenilek AE, Vetkoetter M, Green JM, Shen X, Traylor JG, Klein RL, Orr AW and Woolard MD: Absence of nicotinamide nucleotide transhydrogenase in C57BL/6J mice exacerbates experimental atherosclerosis. J Vasc Res. 55:98–110. 2018. View Article : Google Scholar : PubMed/NCBI
21	Ruscica M, Ferri N, Corsini A and Sirtori CR: PCSK9 antagonists and inflammation. Atherosclerosis. 268:235–236. 2018. View Article : Google Scholar
22	Aarreberg LD, Esser-Nobis K, Driscoll C, Shuvarikov A, Roby JA and Gale M Jr: Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING. Mol Cell. 74:801–815 e806. 2019. View Article : Google Scholar
23	He X, Wang L, Chen XF, Liang Q, Wang WQ, Lin AQ, Yi L, Wang Y and Gao Q: Metformin improved oxidized low-density lipoprotein-impaired mitochondrial function and increased glucose uptake involving akt-AS160 pathway in raw264.7 macro-phages. Chin Med J (Engl). 132:1713–1722. 2019. View Article : Google Scholar
24	Thonusin C, Apaijai N, Jaiwongkam T, Kerdphoo S, Arunsak B, Amput P, Palee S, Pratchayasakul W, Chattipakorn N and Chattipakorn SC: The comparative effects of high dose atorvastatin and proprotein convertase subtilisin/kexin type 9 inhibitor on the mitochondria of oxidative muscle fibers in obese-insulin resistant female rats. Toxicol Appl Pharmacol. 382:1147412019. View Article : Google Scholar : PubMed/NCBI
25	Ding Z, Pothineni NVK, Goel A, Luscher TF and Mehta JL: PCSK9 and inflammation: Role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc Res. 116:908–915. 2020. View Article : Google Scholar
26	Ding Z, Liu S, Wang X, Mathur P, Dai Y, Theus S, Deng X, Fan Y and Mehta JL: Cross-Talk between PCSK9 and damaged mtDNA in vascular smooth muscle cells: Role in apoptosis. Antioxid Redox Signal. 25:997–1008. 2016. View Article : Google Scholar : PubMed/NCBI
27	Massaad CA and Klann E: Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 14:2013–2054. 2011. View Article : Google Scholar :