PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis
-
Saskia R. Desita
,
Arisvia S. Hariftyani
,
Ayik R. Jannah
,
Assyadila K. Setyobudi
and
Yudi H. Oktaviono
Abstract
Coronary artery disease (CAD) is a disease characterized by atherosclerosis formation which causes sudden cardiac death. The prevalence of CAD is expected to increase by 2030. Atherosclerosis started from accumulation of LDL in the blood vessels, followed by endothelial cell activation and dysfunction. PCSK9 is a gene that plays an important role in the creation of atherosclerotic plaque through induced degradation of LDLRs. Inhibition of PCSK9 gene resulted in a decrease of LDLRs degradation and reduction in LDL-C levels. LRP6, as well as its mutation, is a coreceptor that contributes to atherosclerosis through the canonical Wnt/β-catenin pathway. By employing EMPs mediated miRNA-126, third-generation antisense against miR-494-3p (3 GA-494), and recombinant Wnt mouse Wnt3a (rmWnt3a), the inhibition of LRP6 could reduce VSMCs proliferation, enhancing anti-inflammatory macrophages, and diminished bioactive lipids component, respectively. Those mechanisms lead to the stabilization and reduction of atherosclerosis plaques.
Funding source: Universitas Airlangga
Acknowledgments
The author would like to thank the Faculty of Medicine, Universitas Airlangga who support this study.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Not applicable.
-
Ethical approval: Not applicable.
References
1. World Health Organization (WHO). Health statistic information system – causes of death 2000-20016. Geneva; 2016.Search in Google Scholar
2. Khan, MA, Hashim, MJ, Mustafa, H, Baniyas, MY, al Suwaidi, SKBM, AlKatheeri, R, et al.. Global epidemiology of ischemic heart disease: results from the global burden of disease study. Cureus 2020;12:e9349. https://doi.org/10.7759/cureus.9349.Search in Google Scholar PubMed PubMed Central
3. Charla, E, Mercer, J, Maffia, P, Nicklin, SA. Extracellular vesicle signalling in atherosclerosis. Cell Signal 2020;75. https://doi.org/10.1016/j.cellsig.2020.109751.Search in Google Scholar PubMed PubMed Central
4. Palasubramaniam, J, Wang, X, Peter, K. Myocardial infarction – from atherosclerosis to thrombosis: uncovering new diagnostic and therapeutic approaches. Arterioscl Thromb Vasc Biol 2019;39:E176–85. https://doi.org/10.1161/ATVBAHA.119.312578.Search in Google Scholar PubMed
5. Yang, S, Yuan, HQ, Hao, YM, Ren, Z, Qu, SL, Liu, LS, et al.. Macrophage polarization in atherosclerosis. Clin Chim Acta 2020;501:142–6. https://doi.org/10.1016/j.cca.2019.10.034.Search in Google Scholar PubMed
6. Lin, P, Ji, HH, Li, YJ, Guo, SD. Macrophage plasticity and atherosclerosis therapy. Front Mol Biosci 2021;8. https://doi.org/10.3389/fmolb.2021.679797.Search in Google Scholar PubMed PubMed Central
7. Lim, SY. Role of statins in coronary artery disease. Chonnam Med J 2013;49:400–4. https://doi.org/10.4068/cmj.2013.49.1.1.Search in Google Scholar PubMed PubMed Central
8. Mahtta, D, Ramsey, DJ, al Rifai, M, Nasir, K, Samad, Z, Aguilar, D, et al.. Evaluation of aspirin and statin therapy use and adherence in patients with premature atherosclerotic cardiovascular disease. JAMA Netw Open 2020;3: e2011051. https://doi.org/10.1001/jamanetworkopen.2020.11051.Search in Google Scholar PubMed PubMed Central
9. Yebyo, HG, Aschmann, HE, Kaufmann, M, Puhan, MA. Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: a systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J 2019;210:18–28. https://doi.org/10.1016/j.ahj.2018.12.007.Search in Google Scholar PubMed
10. Zimmerman, MP. How do PCSK9 inhibitors stack up to statins for low-density lipoprotein cholesterol control? Am Health Drug Benefits 2015;8:436–42.Search in Google Scholar
11. Pasea, L, Chung, SC, Pujades-Rodriguez, M, Shah, AD, Alvarez-Madrazo, S, Allan, V, et al.. Bleeding in cardiac patients prescribed antithrombotic drugs: electronic health record phenotyping algorithms, incidence, trends and prognosis. BMC Med 2019;17. https://doi.org/10.1186/s12916-019-1438-y.Search in Google Scholar PubMed PubMed Central
12. Handelsman, Y, Lepor, NE. PCSK9 inhibitors in lipid management of patients with diabetes mellitus and high cardiovascular risk: a review. J Am Heart Assoc 2018;7. https://doi.org/10.1161/JAHA.118.008953.Search in Google Scholar PubMed PubMed Central
13. Zhao, Z, Du, S, Shen, S, Luo, P, Ding, S, Wang, G, et al.. Comparative efficacy and safety of lipid-lowering agents in patients with hypercholesterolemia: a frequentist network meta-analysis. Medicine 2019;98:1–12. https://doi.org/10.1097/MD.0000000000014400.Search in Google Scholar PubMed PubMed Central
14. Xu, Y, Gong, W, Peng, J, Wang, H, Huang, J, Ding, H, et al.. Functional analysis LRP6 novel mutations in patients with coronary artery disease. PLoS One 2014;9. https://doi.org/10.1371/journal.pone.0084345.Search in Google Scholar PubMed PubMed Central
15. Kang, S. Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities. Human Genet 2020;139:447–59. https://doi.org/10.1007/s00439-020-02124-8.Search in Google Scholar PubMed
16. Kaddoura, R, Orabi, B, Salam, AM. Efficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update. J Drug Assess 2020;9:129–44. https://doi.org/10.1080/21556660.2020.1801452.Search in Google Scholar PubMed PubMed Central
17. Warden, BA, Fazio, S, Shapiro, MD. The PCSK9 revolution: current status, controversies, and future directions: the PCSK9 revolution. Trends Cardiovasc Med 2020;30:179–85. https://doi.org/10.1016/j.tcm.2019.05.007.Search in Google Scholar PubMed
18. Desai, NR, Giugliano, RP, Zhou, J, Kohli, P, Somaratne, R, Hoffman, E, et al.. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonaL antibody inhibition combined with statin therapy-thrombolysis in myocardial infarction 57). J Am Coll Cardiol 2014;63:430–3. https://doi.org/10.1016/j.jacc.2013.09.048.Search in Google Scholar PubMed
19. Koren, MJ, Sabatine, MS, Giugliano, RP, Langslet, G, Wiviott, SD, Ruzza, A, et al.. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol 2019;74:2132–46. https://doi.org/10.1016/j.jacc.2019.08.1024.Search in Google Scholar PubMed
20. de Mutsert, R, Grootendorst, DC, Indemans, F, Boeschoten, EW, Krediet, RT, Dekker, FW. Association between serum albumin and mortality in dialysis patients is partly explained by inflammation, and not by malnutrition. J Renal Nutr 2009;19:127–35. https://doi.org/10.1053/j.jrn.2008.08.003.Search in Google Scholar PubMed
21. de Mutsert, R, Grootendorst, DC, Indemans, F, Boeschoten, EW, Krediet, RT, Dekker, FW. Association between serum albumin and mortality in dialysis patients is partly explained by inflammation, and not by malnutrition. J Renal Nutr 2009;19:127–35. https://doi.org/10.1053/j.jrn.2008.08.003.Search in Google Scholar
22. Ding, Q, Strong, A, Patel, KM, Ng, SL, Gosis, BS, Regan, SN, et al.. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res 2014;115:488–92. https://doi.org/10.1161/CIRCRESAHA.115.304351.Search in Google Scholar PubMed PubMed Central
23. Langsted, A, Nordestgaard, BG, Benn, M, Tybjærg-Hansen, A, Kamstrup, PR. PCSK9 R46L loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis. J Clin Endocrinol Metatab 2016;101:3281–7. https://doi.org/10.1210/jc.2016-1206.Search in Google Scholar PubMed
24. Joiner, DM, Ke, J, Zhong, Z, Xu, HE, Williams, BO. LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 2013;24:31–9. https://doi.org/10.1016/j.tem.2012.10.003.Search in Google Scholar PubMed PubMed Central
25. Liu, Y, Neogi, A, Mani, A. The role of Wnt signalling in development of coronary artery disease and its risk factors. Open Biol 2020;10:200128. https://doi.org/10.1098/rsob.200128.Search in Google Scholar PubMed PubMed Central
26. Tsaousi, A, Williams, H, Lyon, CA, Taylor, V, Swain, A, Johnson, JL, et al.. Wnt4/β-catenin signaling induces VSMC proliferation and is associated with intimal thickening. Circ Res 2011;108:427–36. https://doi.org/10.1161/CIRCRESAHA.110.233999.Search in Google Scholar PubMed
27. Labbé, P, Thorin, E. Therapeutic targeting of LRP6 in cardiovascular diseases: challenging but not Wnt-possible! Can J Cardiol 2019;35:1567–75. https://doi.org/10.1016/j.cjca.2019.06.030.Search in Google Scholar PubMed
28. Welten, SMJ, Goossens, EAC, Quax, PHA, Nossent, AY. The multifactorial nature of microRNAs in vascular remodelling. Cardiovasc Res 2016;110:6–22. https://doi.org/10.1093/cvr/cvw039.Search in Google Scholar PubMed
29. Wang, X, Lian, Y, Wen, X, Guo, J, Wang, Z, Jiang, S, et al.. Expression of miR-126 and its potential function in coronary artery disease. Afr Health Sci 2017;17:474–80. https://doi.org/10.4314/ahs.v17i2.22.Search in Google Scholar PubMed PubMed Central
30. Dignat-George, F, Boulanger, CM. The many faces of endothelial microparticles. Arterioscl Thromb Vasc Biol 2011;31:27–33. https://doi.org/10.1161/ATVBAHA.110.218123.Search in Google Scholar PubMed
31. Loyer, X, Vion, AC, Tedgui, A, Boulanger, CM. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res 2014;114:345–53. https://doi.org/10.1161/CIRCRESAHA.113.300858.Search in Google Scholar PubMed
32. Hoyer, FF, Giesen, MK, Nunes França, C, Lütjohann, D, Nickenig, G, Werner, N. Monocytic microparticles promote atherogenesis by modulating inflammatory cells in mice. J Cell Mol Med 2012;16:2777–88. https://doi.org/10.1111/j.1582-4934.2012.01595.x.Search in Google Scholar PubMed PubMed Central
33. Jansen, F, Stumpf, T, Proebsting, S, Franklin, BS, Wenzel, D, Pfeifer, P, et al.. Intercellular transfer of miR-126-3p by endothelial microparticles reduces vascular smooth muscle cell proliferation and limits neointima formation by inhibiting LRP6. J Mol Cell Cardiol 2017;104:43–52. https://doi.org/10.1016/j.yjmcc.2016.12.005.Search in Google Scholar PubMed
34. Jansen, F, Yang, X, Proebsting, S, Hoelscher, M, Przybilla, D, Baumann, K, et al.. MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. J Am Heart Assoc 2014;3. https://doi.org/10.1161/JAHA.114.001249.Search in Google Scholar PubMed PubMed Central
35. Tabas, I, Bornfeldt, KE. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res 2016;118:653–67. https://doi.org/10.1161/CIRCRESAHA.115.306256.Search in Google Scholar PubMed PubMed Central
36. Stöger, JL, Gijbels, MJJ, van der Velden, S, Manca, M, van der Loos, CM, Biessen, EAL, et al.. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis 2012;225:461–8. https://doi.org/10.1016/j.atherosclerosis.2012.09.013.Search in Google Scholar PubMed
37. van Ingen, E, Foks, AC, Woudenberg, T, van der Bent, ML, de Jong, A, Hohensinner, PJ, et al.. Inhibition of microRNA-494-3p activates Wnt signaling and reduces proinflammatory macrophage polarization in atherosclerosis. Mol Ther – Nucleic Acids 2021;26:1228–39. https://doi.org/10.1016/j.omtn.2021.10.027.Search in Google Scholar PubMed PubMed Central
38. Mani, A, Radhakrishnan, J, Wang, H, Mani, A, Mani, MA, Nelson-Williams, C, et al.. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 2007;315:1278–82. https://doi.org/10.1126/science.1136370.Search in Google Scholar PubMed PubMed Central
39. Singh, R, Smith, E, Fathzadeh, M, Liu, W, Go, GW, Subrahmanyan, L, et al.. Rare nonconservative LRP6 mutations are associated with metabolic syndrome. Hum Mutation 2013;34:1221–5. https://doi.org/10.1002/humu.22360.Search in Google Scholar PubMed PubMed Central
40. Go, GW, Srivastava, R, Hernandez-Ono, A, Gang, G, Smith, SB, Booth, CJ, et al.. The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metabol 2014;19:209–20. https://doi.org/10.1016/j.cmet.2013.11.023.Search in Google Scholar PubMed PubMed Central
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Circulating tumor cells in bladder cancer: a new horizon of liquid biopsy for precision medicine
- Minireview
- PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis
- Reviews
- The complex relationship between physical activity and diabetes: an overview
- Methotrexate related cutaneous adverse drug reactions: a systematic literature review
- Long-term use of proton pump inhibitors adversely affects minerals and vitamin metabolism, bone turnover, bone mass, and bone strength
- An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics
- Original Articles
- Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties
- Are hypertensive patients with history of coronary artery disease at risk for silent lower extremity artery disease?
- The effect of long-term ketogenic diet on serum adiponectin and insulin-like growth factor-1 levels in mice
- Increase in cardioprotective SUR2A does not alter heart rate and heart rate regulation by physical activity and diurnal rhythm
- Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study
- Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice
- Modern gold standard of cardiac output measurement – A simplified bedside measurement of individual oxygen uptake in the cath lab
- Electrical vestibular nerve stimulation (VeNS): a follow-up safety assessment of long-term usage
- Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity
- Limited diagnostic value of questionnaire-based pre-participation screening algorithms: a “risk-exposed” approach to sports activity
- Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome
Articles in the same Issue
- Frontmatter
- Editorial
- Circulating tumor cells in bladder cancer: a new horizon of liquid biopsy for precision medicine
- Minireview
- PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis
- Reviews
- The complex relationship between physical activity and diabetes: an overview
- Methotrexate related cutaneous adverse drug reactions: a systematic literature review
- Long-term use of proton pump inhibitors adversely affects minerals and vitamin metabolism, bone turnover, bone mass, and bone strength
- An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics
- Original Articles
- Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties
- Are hypertensive patients with history of coronary artery disease at risk for silent lower extremity artery disease?
- The effect of long-term ketogenic diet on serum adiponectin and insulin-like growth factor-1 levels in mice
- Increase in cardioprotective SUR2A does not alter heart rate and heart rate regulation by physical activity and diurnal rhythm
- Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study
- Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice
- Modern gold standard of cardiac output measurement – A simplified bedside measurement of individual oxygen uptake in the cath lab
- Electrical vestibular nerve stimulation (VeNS): a follow-up safety assessment of long-term usage
- Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity
- Limited diagnostic value of questionnaire-based pre-participation screening algorithms: a “risk-exposed” approach to sports activity
- Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome
