Research progress of proprotein convertase subtilisin/kexin type 9 in atherosclerotic cardiovascular disease_West China Medical Journal

Authors：

ZHOU Yangyang ,  WEI Wei

Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

WEI Wei, Email: ww8075@126.com

Keywords：

Proprotein convertase subtilisin/kexin type 9; atherosclerotic cardiovascular disease; Lipid regulation; platelet activation; inflammatory response; apoptosis; autophagy and pyroptosis

DOI：

10.7507/1002-0179.202409217

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Atherosclerotic cardiovascular disease (ASCVD) is a disease caused by the accumulation of atherosclerotic plaques that leads to arterial hardening and impairment of contractility. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can increase low-density lipoprotein cholesterol levels in plasma, which accelerates the development and progression of ASCVD. This article intends to review the biological characteristics and functional mechanisms of PCSK9, elucidate its impact on the development and progression of ASCVD, provide research literature support for the diagnosis and treatment of such diseases and improving the prognosis of patients.

1.	Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol, 2019, 73(24): e285-e350.
2.	中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2022 概要. 中国循环杂志, 2023, 38(6): 583-612.
3.	Bäck M, Yurdagul A Jr, Tabas I, et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol, 2019, 16(7): 389-406.
4.	Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A, 2003, 100(3): 928-933.
5.	Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol, 2014, 25(5): 387-393.
6.	Andreadou I, Tsoumani M, Vilahur G, et al. PCSK9 in myocardial infarction and cardioprotection: importance of lipid metabolism and inflammation. Front Physiol, 2020, 11: 602497.
7.	Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A, 2005, 102(6): 2069-2074.
8.	Badimon L, Padró T, Vilahur G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care, 2012, 1(1): 60-74.
9.	Kon V, Yang HC, Smith LE, et al. High-density lipoproteins in kidney disease. Int J Mol Sci, 2021, 22(15): 8201.
10.	Linton MF, Yancey PG, Tao H, et al. HDL function and atherosclerosis: reactive dicarbonyls as promising targets of therapy. Circ Res, 2023, 132(11): 1521-1545.
11.	Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell, 2015, 161(1): 161-172.
12.	Luquero A, Badimon L, Borrell-Pages M. PCSK9 functions in atherosclerosis are not limited to plasmatic LDL-cholesterol regulation. Front Cardiovasc Med, 2021, 8: 639727.
13.	Kudo T, Sasaki K, Tada H. Familial hypobetalipoproteinemia caused by homozygous loss-of-function mutations in PCSK9: a case report. J Clin Lipidol, 2022, 16(5): 596-600.
14.	Ragusa R, Basta G, Neglia D, et al. PCSK9 and atherosclerosis: looking beyond LDL regulation. Eur J Clin Invest, 2021, 51(4): e13459.
15.	Valenti V, Noto D, Giammanco A, et al. PCSK9-D374Y mediated LDL-R degradation can be functionally inhibited by EGF-A and truncated EGF-A peptides: an in vitro study. Atherosclerosis, 2020, 292: 209-214.
16.	Emma MR, Giannitrapani L, Cabibi D, et al. Hepatic and circulating levels of PCSK9 in morbidly obese patients: relation with severity of liver steatosis. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(12): 158792.
17.	Abujrad H, Mayne J, Ruzicka M, et al. Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels. Atherosclerosis, 2014, 233(1): 123-129.
18.	Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol, 2005, 25(12): 2654-2660.
19.	Pham NH, Truong PK, Lao TD, et al. Proprotein convertase subtilisin/kexin type 9 gene variants in familial hypercholesterolemia: a systematic review and meta-analysis. Processes, 2021, 9(2): 283.
20.	Sun H, Samarghandi A, Zhang N, et al. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein Band prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler ThrombVasc Biol, 2012, 32(7): 1585-1595.
21.	Croyal M, Blanchard V, Ouguerram K, et al. VLDL (very-low-density lipoprotein)-Apo E (apolipoprotein E) may influence Lp (a)(lipoprotein [a]) synthesis or assembly. Arterioscler Thromb Vasc Biol, 2020, 40(3): 819-829.
22.	Chernogubova E, Strawbridge R, Mahdessian H, et al. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol, 2012, 32(6): 1526-1534.
23.	Chang YC, Hsu LA, Ko YL. Exploring PCSK9 genetic impact on lipoprotein (a) via dual approaches: association and mendelian randomization. Int J Mol Sci, 2023, 24(19): 14668.
24.	Qi Z, Hu L, Zhang J, et al. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation, 2021, 143(1): 45-61.
25.	Cammisotto V, Baratta F, Castellani V, et al. Proprotein convertase subtilisin kexin type 9 inhibitors reduce platelet activation modulating ox-LDL pathways. Int J Mol Sci, 2021, 22(13): 7193.
26.	Puteri MU, Azmi NU, Kato M, et al. PCSK9 promotes cardiovascular diseases: recent evidence about its association with platelet activation-induced myocardial infarction. Life (Basel), 2022, 12(2): 190.
27.	Carvalho AC, Colman RW, Lees RS. Platelet function in hyperlipoproteinemia. N Engl J Med, 1974, 290(8): 434-438.
28.	Sparks RP, Arango AS, Jenkins JL, et al. An allosteric binding site on sortilin regulates the trafficking of VLDL, PCSK9, and LDLR in hepatocytes. Biochemistry, 2020, 59(45): 4321-4335.
29.	Barale C, Bonomo K, Frascaroli C, et al. Platelet function and activation markers in primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: a 12-month follow-up. Nutr Metab Cardiovasc Dis, 2020, 30(2): 282-291.
30.	Camera M, Rossetti L, Barbieri SS, et al. PCSK9 as a positive modulator of platelet activation. J Am Coll Cardiol, 2018, 71(8): 952-954.
31.	Madjid M, Fatemi O. Components of the complete blood count as risk predictors for coronary heart disease: in-depth review and update. Tex Heart Inst J, 2013, 40(1): 17-29.
32.	Li S, Guo YL, Xu RX, et al. Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis, 2014, 234(2): 441-445.
33.	Zhang Y, Zhu CG, Xu RX, et al. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J Clin Lipidol, 2014, 8(5): 494-500.
34.	Aceña Á, Franco Peláez JA, Pello Lázaro AM, et al. PCSK9 and HS-CRP predict progression of aortic stenosis in patients with stable coronary artery disease. J Cardiovasc Transl Res, 2021, 14(2): 238-245.
35.	Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk trial. Am Heart J, 2016, 173: 94-101.
36.	Yuan J, Cai T, Zheng X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell, 2021, 12(4): 240-260.
37.	Barreto J, Karathanasis SK, Remaley A, et al. Role of LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) as a cardiovascular risk predictor: mechanistic insight and potential clinical use. Arterioscler Thromb Vasc Biol, 2021, 41(1): 153-166.
38.	Li J, Liang X, Wang Y, et al. Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep, 2017, 16(2): 1817-1825.
39.	Ding Z, Wang X, Liu S, et al. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc Res, 2018, 114(13): 1738-1751.
40.	Choumar A, Tarhuni A, Lettéron P, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal, 2011, 15(11): 2837-2854.
41.	Oka T, Hikoso S, Yamaguchi O, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature, 2012, 485(7397): 251-255.
42.	Wang X, Li X, Liu S, et al. PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia. Basic Res Cardiol, 2020, 115(6): 66.
43.	Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722.

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol, 2019, 73(24): e285-e350.
2. 中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2022 概要. 中国循环杂志, 2023, 38(6): 583-612.
3. Bäck M, Yurdagul A Jr, Tabas I, et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol, 2019, 16(7): 389-406.
4. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A, 2003, 100(3): 928-933.
5. Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol, 2014, 25(5): 387-393.
6. Andreadou I, Tsoumani M, Vilahur G, et al. PCSK9 in myocardial infarction and cardioprotection: importance of lipid metabolism and inflammation. Front Physiol, 2020, 11: 602497.
7. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A, 2005, 102(6): 2069-2074.
8. Badimon L, Padró T, Vilahur G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care, 2012, 1(1): 60-74.
9. Kon V, Yang HC, Smith LE, et al. High-density lipoproteins in kidney disease. Int J Mol Sci, 2021, 22(15): 8201.
10. Linton MF, Yancey PG, Tao H, et al. HDL function and atherosclerosis: reactive dicarbonyls as promising targets of therapy. Circ Res, 2023, 132(11): 1521-1545.
11. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell, 2015, 161(1): 161-172.
12. Luquero A, Badimon L, Borrell-Pages M. PCSK9 functions in atherosclerosis are not limited to plasmatic LDL-cholesterol regulation. Front Cardiovasc Med, 2021, 8: 639727.
13. Kudo T, Sasaki K, Tada H. Familial hypobetalipoproteinemia caused by homozygous loss-of-function mutations in PCSK9: a case report. J Clin Lipidol, 2022, 16(5): 596-600.
14. Ragusa R, Basta G, Neglia D, et al. PCSK9 and atherosclerosis: looking beyond LDL regulation. Eur J Clin Invest, 2021, 51(4): e13459.
15. Valenti V, Noto D, Giammanco A, et al. PCSK9-D374Y mediated LDL-R degradation can be functionally inhibited by EGF-A and truncated EGF-A peptides: an in vitro study. Atherosclerosis, 2020, 292: 209-214.
16. Emma MR, Giannitrapani L, Cabibi D, et al. Hepatic and circulating levels of PCSK9 in morbidly obese patients: relation with severity of liver steatosis. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(12): 158792.
17. Abujrad H, Mayne J, Ruzicka M, et al. Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels. Atherosclerosis, 2014, 233(1): 123-129.
18. Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol, 2005, 25(12): 2654-2660.
19. Pham NH, Truong PK, Lao TD, et al. Proprotein convertase subtilisin/kexin type 9 gene variants in familial hypercholesterolemia: a systematic review and meta-analysis. Processes, 2021, 9(2): 283.
20. Sun H, Samarghandi A, Zhang N, et al. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein Band prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler ThrombVasc Biol, 2012, 32(7): 1585-1595.
21. Croyal M, Blanchard V, Ouguerram K, et al. VLDL (very-low-density lipoprotein)-Apo E (apolipoprotein E) may influence Lp (a)(lipoprotein [a]) synthesis or assembly. Arterioscler Thromb Vasc Biol, 2020, 40(3): 819-829.
22. Chernogubova E, Strawbridge R, Mahdessian H, et al. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol, 2012, 32(6): 1526-1534.
23. Chang YC, Hsu LA, Ko YL. Exploring PCSK9 genetic impact on lipoprotein (a) via dual approaches: association and mendelian randomization. Int J Mol Sci, 2023, 24(19): 14668.
24. Qi Z, Hu L, Zhang J, et al. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation, 2021, 143(1): 45-61.
25. Cammisotto V, Baratta F, Castellani V, et al. Proprotein convertase subtilisin kexin type 9 inhibitors reduce platelet activation modulating ox-LDL pathways. Int J Mol Sci, 2021, 22(13): 7193.
26. Puteri MU, Azmi NU, Kato M, et al. PCSK9 promotes cardiovascular diseases: recent evidence about its association with platelet activation-induced myocardial infarction. Life (Basel), 2022, 12(2): 190.
27. Carvalho AC, Colman RW, Lees RS. Platelet function in hyperlipoproteinemia. N Engl J Med, 1974, 290(8): 434-438.
28. Sparks RP, Arango AS, Jenkins JL, et al. An allosteric binding site on sortilin regulates the trafficking of VLDL, PCSK9, and LDLR in hepatocytes. Biochemistry, 2020, 59(45): 4321-4335.
29. Barale C, Bonomo K, Frascaroli C, et al. Platelet function and activation markers in primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: a 12-month follow-up. Nutr Metab Cardiovasc Dis, 2020, 30(2): 282-291.
30. Camera M, Rossetti L, Barbieri SS, et al. PCSK9 as a positive modulator of platelet activation. J Am Coll Cardiol, 2018, 71(8): 952-954.
31. Madjid M, Fatemi O. Components of the complete blood count as risk predictors for coronary heart disease: in-depth review and update. Tex Heart Inst J, 2013, 40(1): 17-29.
32. Li S, Guo YL, Xu RX, et al. Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis, 2014, 234(2): 441-445.
33. Zhang Y, Zhu CG, Xu RX, et al. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J Clin Lipidol, 2014, 8(5): 494-500.
34. Aceña Á, Franco Peláez JA, Pello Lázaro AM, et al. PCSK9 and HS-CRP predict progression of aortic stenosis in patients with stable coronary artery disease. J Cardiovasc Transl Res, 2021, 14(2): 238-245.
35. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk trial. Am Heart J, 2016, 173: 94-101.
36. Yuan J, Cai T, Zheng X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell, 2021, 12(4): 240-260.
37. Barreto J, Karathanasis SK, Remaley A, et al. Role of LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) as a cardiovascular risk predictor: mechanistic insight and potential clinical use. Arterioscler Thromb Vasc Biol, 2021, 41(1): 153-166.
38. Li J, Liang X, Wang Y, et al. Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep, 2017, 16(2): 1817-1825.
39. Ding Z, Wang X, Liu S, et al. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc Res, 2018, 114(13): 1738-1751.
40. Choumar A, Tarhuni A, Lettéron P, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal, 2011, 15(11): 2837-2854.
41. Oka T, Hikoso S, Yamaguchi O, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature, 2012, 485(7397): 251-255.
42. Wang X, Li X, Liu S, et al. PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia. Basic Res Cardiol, 2020, 115(6): 66.
43. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722.

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Latest ArticlesResearch progress of proprotein convertase subtilisin/kexin type 9 in atherosclerotic cardiovascular disease

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