Proprotein Convertase Subtilisin/Kexin 9 as a Modifier of Lipid Metabolism in Atherosclerosis
Open accessAbstract
Despite being the most common treatment strategy in the management of atherosclerosis and subsequent cardiovascular disease, classical statin therapy has certain disadvantages, including numerous side effects. In addition, a regimen with daily administration of the drug is hard to comply with. Thus, there is a need for modern and more efficient therapeutic strategies in CVD treatment. There is extensive evidence indicating that PCSK9 promotes atherogenesis through a variety of mechanisms. Thus, new treatment methods can be developed that prevent or alleviate atherosclerotic cardiovascular disease by targeting PCSK9. Comprehensive understanding of its atherogenic properties is a necessary precondition for the establishment of new therapeutic strategies. In this review, we will summarize the available data on the role of PCSK9 in the development and progression of atherosclerosis. In the last section, we will consider existing PCSK9 inhibitors.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Inclisiran targets messenger RNA (mRNA) of proprotein convertase subtilisin/kexin type 9 (PCSK9) within hepatocytes to decrease PCSK9 synthesis at the transcriptional level.
“Through its application of RNA interference (RNAi) technology Inclisiran targets messenger RNA (mRNA) of proprotein convertase subtilisin/kexin type 9 (PCSK9) within hepatocytes to decrease PCSK9 synthesis at the transcriptional level [64, 65].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [65]
Section 5 says inclisiran is a small interfering RNA taken up by liver cells; its guide strand directs cleavage and degradation of PCSK9 mRNA, preventing hepatic PCSK9 synthesis. That supports the target and effect, but not the claim that it acts at the transcriptional level: the described action is on mRNA after transcription. No page number is provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Momtazi‐Borojeni, A. A., Jaafari, M. R., Badiee, A., Banach, M., & Sahebkar, A. (2019) · BMC Medicine · doi:10.1186/s12916-019-1457-8 · Cited by 64 · cited 1× · see citing works
“In addition, the doses can be administered less frequently and the total treatment cost is lower [41].”
BackgroundRetractedThe Nuclear Factor NF- B Pathway in InflammationPreprint
Lawrence, T. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001651 · Cited by 4,926 · cited 1× · see citing works
“PCSK9-mediated ox-LDL efflux depends on NF-KB, damaged mitochondrial DNA, and mitogen-activated protein kinase [34].”
BackgroundBorén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601 · see citing works
Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities
Bäck, M., Yurdagul, A., Tabas, I., Öörni, K., & Kovanen, P. T. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0169-2 · Cited by 1,341 · see citing works
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., Hall, T., Troquay, R. P. T., Turner, T., Visseren, F. L. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615758 · Cited by 992 · see citing works
Giugliano, R. P., Pedersen, T. R., Park, J.-G., De Ferrari, G. M., Gaciong, Z. A., Ceska, R., Toth, K., Gouni-Berthold, I., Lopez-Miranda, J., Schiele, F., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32290-0 · Cited by 682 · cited 2× · see citing works
“FOURIER Evolocumab (with statins) 140 mg biweekly or 420 mg monthly 27,564 ASCVD patients Reduction by 60% [51]”
BackgroundMonocyte-macrophages and T cells in atherosclerosis
Tabas, I., & Lichtman, A. H. (2017) · Immunity · doi:10.1016/j.immuni.2017.09.008 · Cited by 646 · cited 1× · see citing works
“If PCSK9 is silenced, it reduces the secretion of interleukin-1β, TNF-α, and monocyte chemoattractant protein 1 in the arteries of ApoE KO mice with atherosclerosis [32].”
BackgroundMolecular biology of PCSK9: its role in LDL metabolism
HORTON, J., COHEN, J., & HOBBS, H. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.12.008 · Cited by 621 · cited 1× · see citing works
“Studies have shown that individuals with GOF mutations in PCSK9 demonstrate elevated plasma Lp(a) levels [29].”
BackgroundMcKenney, J. M., Koren, M. J., Kereiakes, D. J., Hanotin, C., Ferrand, A.-C., & Stein, E. A. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.03.007 · Cited by 507 · cited 1× · see citing works
“7% by evolocumab [60], 13–29% by alirocumab [61,62], and 18.”
BackgroundPoirier, S., Mayer, G., Benjannet, S., Bergeron, E., Marcinkiewicz, J., Nassoury, N., Mayer, H., Nimpf, J., Prat, A., & Seidah, N. G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708098200 · Cited by 477 · cited 1× · see citing works
“This makes PCSK9 an attractive target for developing cancer therapies [8].”
BackgroundMolecular basis for LDL receptor recognition by PCSK9
Kwon, H. J., Lagace, T. A., McNutt, M., Horton, J. D., & Deisenhofer, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712064105 · Cited by 418 · cited 1× · see citing works
“PCSK9 is responsible for the degradation of both LDLR and structurally similar receptors, such as VLDLR and ApoER2, since all these receptors include an epidermal growth factor-like repeat A (EGF-A) domain which PCSK9 binds to and targets the complex for lysosomal degradation [21].”
BackgroundPCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells
Lagace, T. A. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000114 · Cited by 372 · cited 1× · see citing works
“5 h halftime and 5 h halftime dissociation) [11].”
BackgroundRay, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30158-5 · Cited by 315 · see citing works
New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway
Tang, Z.-H., Peng, J., Ren, Z., Yang, J., Li, T.-T., Li, T.-H., Wang, Z., Wei, D.-H., Liu, L.-S., Zheng, X.-L., et al. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.04.023 · Cited by 291 · cited 1× · see citing works
“Thus, NF-KB is responsible for the signaling in the inflammatory pathway involving PCSK9 expression, and the TLR4/NF-KB pathway plays an important role in the PCSK9-induced inflammation of atherosclerotic plaques [35].”
BackgroundPCSK9: From Basic Science Discoveries to Clinical Trials
Shapiro, M. D., Tavori, H., & Fazio, S. (2018) · Circulation Research · doi:10.1161/circresaha.118.311227 · Cited by 285 · cited 1× · see citing works
“These mAbs markedly, up to 60 to 70 per cent, lower circulating LDL-C, which significantly reduces the risks of cardiovascular disease [56].”
BackgroundPCSK9 induces a pro-inflammatory response in macrophages
Ricci, C., Ruscica, M., Camera, M., Rossetti, L., Macchi, C., Colciago, A., Zanotti, I., Lupo, M. G., Adorni, M. P., Cicero, A. F. G., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20425-x · Cited by 227 · cited 2× · see citing works
“This activates LDLRs and PCSK9 gene expression, and increases circulating PCSK9 levels.”
BackgroundRaal, F. J., Giugliano, R. P., Sabatine, M. S., Koren, M. J., Blom, D. J., Seidah, N. G., Honarpour, N., Lira, A., Xue, A. X., Chiruvolu, P., et al. (2016) · Journal of Lipid Research · doi:10.1016/j.jlr.2026.101063 · Cited by 222 · see citing works
Gaudet, D., Kereiakes, D. J., McKenney, J. M., Roth, E. M., Hanotin, C., Gipe, D. A., Du, Y. E., Ferrand, A.-C., Ginsberg, H. N., & Stein, E. A. (2014) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2014.05.060 · Cited by 210 · cited 1× · see citing works
“7% by evolocumab [60], 13–29% by alirocumab [61,62], and 18.”
BackgroundPCSK9 Biology and Its Role in Atherothrombosis
Barale, C., Melchionda, E., Morotti, A., & Russo, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115880 · Cited by 176 · cited 1× · see citing works
“LDLR in its turn, is involved in PCSK9 homeostasis as it mediates its clearance from plasma, irrespective of the PCSK9 tissue origin [10].”
BackgroundPCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages
Ding, Z., Liu, S., Wang, X., Theus, S., Deng, X., Fan, Y., Zhou, S., & Mehta, J. L. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy079 · Cited by 147 · cited 1× · see citing works
“Thus, PCSK9 can be considered a promising target in the treatment of atherosclerotic plaques [39].”
BackgroundRashid, S., Tavori, H., Brown, P. E., Linton, M. F., He, J., Giunzioni, I., & Fazio, S. (2014) · Circulation · doi:10.1161/circulationaha.113.006720 · Cited by 138 · see citing works
Regulation of PCSK9 by nutraceuticals
Momtazi, A. A., Banach, M., Pirro, M., Katsiki, N., & Sahebkar, A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.03.023 · Cited by 131 · cited 1× · see citing works
“However, the interaction of these receptors with PCSK9 does not always result in their degradation [15,16].”
BackgroundLipid lowering therapy and circulating PCSK9 concentration
Nozue, T. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17012 · Cited by 127 · cited 1× · see citing works
“This is a potential mechanism of limitation of the efficacy of statin-induced LDL-C reduction, which can explain the “6% rule for statins”, which states that the doubling of a statin dose brings only approximately 6% additional reduction in LDL-C level [49,50].”
BackgroundRegulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications
Xia, X.-D., Peng, Z.-S., Gu, H.-M., Wang, M., Wang, G.-Q., & Zhang, D.-W. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.764038 · Cited by 125 · cited 1× · see citing works
“However, it remains non-covalently bound to the rest of the mature protein, promoting PCSK9 folding and blocking its catalytic domain [6].”
BackgroundSmall Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9
German, C. A., & Shapiro, M. D. (2019) · BioDrugs · doi:10.1007/s40259-019-00399-6 · Cited by 115 · cited 1× · see citing works
“Significantly reducing PCSK9 production in the liver, it promotes marked LDL-C reduction, preserving its therapeutic effects for six months after a subcutaneous injection [68].”
BackgroundTavori, H., Giunzioni, I., Predazzi, I. M., Plubell, D. L., Shivinsky, A., Miles, J., DeVay, R. M., Hong, L., Rashid, S., Linton, M. F., et al. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw053 · Cited by 114 · cited 1× · see citing works
“GOF PCSK9 variations in humans, such as the Asp substitution with Tyr (PCSK9D374Y), result in severe phenotypes with cholesterol concentrations above 500 mg/dL (~13 mmol/L) [26].”
BackgroundAn Update on the Role of PCSK9 in Atherosclerosis
Yurtseven, E., Ural, D., Baysal, K., & Tokgözoğlu, L. S. (2020) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.55400 · Cited by 113 · cited 1× · see citing works
“Inhibition of PCSK9 in dendritic cells results in lower proliferation and differentiation of T-cells [37].”
BackgroundLebeau, P. F., Byun, J. H., Platko, K., Saliba, P., Sguazzin, M. A., MacDonald, M. E., Paré, G., Steinberg, G. R., Janssen, L. J., Igdoura, S. A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28240-9 · Cited by 112 · cited 1× · see citing works
“Similarly, higher postprandial insulin levels promote PCSK9 mRNA synthesis as a result of SREBP1 activation [3,4].”
BackgroundPCSK9 Inhibition: From Current Advances to Evolving Future
Liu, C., Chen, J., Chen, H., Zhang, T., He, D., Luo, Q., Chi, J., Hong, Z., Liao, Y., Zhang, S., et al. (2022) · Cells · doi:10.3390/cells11192972 · Cited by 106 · cited 1× · see citing works
“According to recent studies, PCSK9 inhibitors may be useful in the treatment of sepsis, certain tumors, certain viral infections, and other diseases [75].”
BackgroundJang, H., Lee, S. E., Yang, J., Lee, H.-C., Shin, D., Lee, H., Lee, J., Jin, S., Kim, S., Lee, S. J., et al. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz566 · Cited by 99 · cited 3× · see citing works
“PCSK9 binds to LDLR via its catalytic domain and interacts with CAP1 via CHRD, promoting the lysosomal degradation of protein complex LDLR/PCSK9/CAP1 by means of the caveolin pathway.”
BackgroundInfluentialPhysiological and therapeutic regulation of PCSK9 activity in cardiovascular disease
Glerup, S., Schulz, R., Laufs, U., & Schlüter, K. (2017) · Basic Research in Cardiology · doi:10.1007/s00395-017-0619-0 · Cited by 92 · cited 1× · see citing works
“Similarly, the association between sortilin 1 (SORT1) and PCSK9 in the trans-Golgi is essential for the inactive protease expression through the blood [7].”
BackgroundUnmet Needs in LDL-C Lowering: When Statins Won’t Do!
Krähenbühl, S., Pavik-Mezzour, I., & von Eckardstein, A. (2016) · Drugs · doi:10.1007/s40265-016-0613-0 · Cited by 89 · see citing works
Duan, Y., Chen, Y., Hu, W., Li, X., Yang, X., Zhou, X., Yin, Z., Kong, D., Yao, Z., Hajjar, D. P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.350181 · Cited by 87 · cited 1× · see citing works
“Finally, PCSK9 gene expression can be regulated by sirtuin 1 and 6 (SIRT1 and SIRT6), which can silence the PCSK9 gene [5].”
BackgroundMerćep, I., Friščić, N., Strikić, D., & Reiner, Ž. (2022) · Cardiovascular Therapeutics · doi:10.1155/2022/8129513 · Cited by 85 · see citing works
NLRP3 inflammasome via IL-1β regulates PCSK9 secretion
Ding, Z., Wang, X., Liu, S., Zhou, S., Kore, R. A., Mu, S., Deng, X., Fan, Y., & Mehta, J. L. (2020) · Theranostics · doi:10.7150/thno.45939 · Cited by 79 · cited 1× · see citing works
“Furthermore, it decreased the expression of NLRP3 inflammasome in macrophages, leading to suppressed macrophage PCSK9 secretion and slower development of atherosclerosis [42].”
BackgroundThe genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations
Civeira, F. (2010) · The Application of Clinical Genetics · doi:10.2147/tacg.s8285 · Cited by 76 · see citing works
Pastori, D., Nocella, C., Farcomeni, A., Bartimoccia, S., Santulli, M., Vasaturo, F., Carnevale, R., Menichelli, D., Violi, F., Pignatelli, P., et al. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.07.743 · Cited by 76 · cited 1× · see citing works
“The study was conducted on patients with a high risk of cardiovascular complications [45].”
BackgroundExpanding biology of PCSK9: roles in atherosclerosis and beyond
Seidah, N. G., & Garçon, D. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01057-z · Cited by 76 · cited 1× · see citing works
“The activation of each of these pathways depends on the PCSK9 binding partner [12,13].”
BackgroundPCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation
Luquero, A., Badimón, L., & Borrell-Pagés, M. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.639727 · Cited by 73 · cited 3× · see citing works
“In inflammation, expression of the vascular cell adhesion molecule 1 (VCAM-1) is increased.”
BackgroundPCSK9 signaling pathways and their potential importance in clinical practice
Wiciński, M., Żak, J., Malinowski, B., Popek, G., & Grześk, G. (2017) · The EPMA Journal · doi:10.1007/s13167-017-0106-6 · Cited by 69 · see citing works
PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology
Sundararaman, S. S., Döring, Y., & van der Vorst, E. P. C. (2021) · Biomedicines · doi:10.3390/biomedicines9070793 · Cited by 67 · cited 1× · see citing works
“Another polyphenol, quercetin, on the contrary, is able to activate SREBP2 transcription, increasing the expression of the LDLR gene and reducing the expression of PCSK9 [74].”
BackgroundWang, X., Wen, D., Chen, Y., Ma, L., & You, C. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01542-4 · Cited by 67 · cited 1× · see citing works
“According to them, inhibitors of PCSK9 are recommended for patients with clinically evident atherosclerotic cardiovascular disease and LDL-C ≥ 90 mg/dL in spite of statin treatment in maximal tolerated doses with or without ezetimibe [64].”
BackgroundNicholls, S. J., Nissen, S. E., Prati, F., Windecker, S., Kataoka, Y., Puri, R., Hucko, T., Kassahun, H., Liao, J., Somaratne, R. M., et al. (2021) · Cardiovascular Diagnosis and Therapy · doi:10.21037/cdt-20-684 · Cited by 65 · cited 1× · see citing works
“In atherogenic murine models, PCSK9 inhibition increased the number of circulating angiogenic cells as well as endothelial progenitor cells, which is a marker of vascular health and a predictor of decreased cardiovascular risk [43].”
BackgroundNishikido, T., & Ray, K. K. (2019) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2018.00199 · Cited by 62 · cited 1× · see citing works
“Thus, several PCSK9 mRNAs can be degraded by a single inclisiran–RISC complex [71].”
BackgroundPCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis
Guo, Q., Feng, X., & Zhou, Y. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.01020 · Cited by 58 · cited 1× · see citing works
“Such mutations can be observed relatively often and have been recapitulated in both in vivo and in vitro experiments [27].”
BackgroundLi, S., Zhu, C., Guo, Y., Xu, R., Zhang, Y., Sun, J., & Li, J. (2014) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.25841 · Cited by 57 · cited 1× · see citing works
“, in their cross-sectional study, found for the first time that there was a positive and independent association between plasma PCSK9 levels and platelet counts in 330 patients with stable CAD, suggesting an association between high PCSK9 levels, platelets, atherosclerosis, and cardiovascular disease [44].”
BackgroundSafety and Tolerability of PCSK9 Inhibitors: Current Insights
Kosmas, C. E., Skavdis, A., Sourlas, A., Papakonstantinou, E. J., Genao, E. P., Uceta, R. E., & Guzman, E. (2020) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s288831 · Cited by 53 · cited 1× · see citing works
“As soon as PCSK9′s role in cholesterol homeostasis had been discovered, there appeared interest to create therapies targeting its pathway which could be used in hypercholesterolemia treatment [48].”
BackgroundThe PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol
Seidah, N. G. (2017) · Global Cardiology Science and Practice · doi:10.21542/gcsp.2017.2 · Cited by 51 · cited 1× · see citing works
“Although the PCSK9/LDLR interaction primarily happens through the catalytic domain of PCSK9, the majority of PCSK9 mutations in humans occur in the CHRD (n = 22; 30%), prodomain (n = 21; 28%), or the SP (n = 7; 10%) [24].”
BackgroundTreatment patterns and patient characteristics among early initiators of PCSK9 inhibitors
Hines, D. M., Rane, P., Patel, J. G., Harrison, D. J., & Wade, R. L. (2018) · Vascular Health and Risk Management · doi:10.2147/vhrm.s180496 · Cited by 45 · cited 1× · see citing works
“Moreover, a current in-depth analysis of data on real-world adherence to and persistence with LLT in Germany demonstrated a rate of treatment discontinuation of 50% after 36 months [66,67].”
BackgroundMbikay, M., Mayne, J., Sirois, F., Fedoryak, O. D., Raymond, A., Noad, J., & Chrétien, M. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700729 · Cited by 44 · cited 1× · see citing works
“However, the interaction of these receptors with PCSK9 does not always result in their degradation [15,16].”
BackgroundInsight into the Evolving Role of PCSK9
Maligłówka, M., Kosowski, M., Hachuła, M., Cyrnek, M., Bułdak, Ł., Basiak, M., Bołdys, A., Machnik, G., Bułdak, R. J., & Okopień, B. (2022) · Metabolites · doi:10.3390/metabo12030256 · Cited by 41 · see citing works
Papotti, B., Adorni, M. P., Marchi, C., Zimetti, F., Ronda, N., Panighel, G., Lupo, M. G., Vilella, A., Giuliani, D., Ferri, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012192 · Cited by 41 · cited 1× · see citing works
“This new pharmacological approach, focused on the lipid hypothesis of AD pathogenesis, will open up new perspectives for AD, for which there are currently no available therapies [9].”
BackgroundKatzmann, J. L., Cupido, A. J., & Laufs, U. (2022) · Metabolites · doi:10.3390/metabo12010070 · Cited by 40 · cited 1× · see citing works
“Since December 2020, it has been approved for use in the EU [73].”
BackgroundPiccinni, C. P., Antonazzo, I. C., Maggioni, A. P., Pedrini, A., Calabria, S., Ronconi, G., Dondi, L., Martini, N., Roberto, G., Sampietro, T., et al. (2019) · Clinical Drug Investigation · doi:10.1007/s40261-019-00877-3 · Cited by 39 · cited 1× · see citing works
“Moreover, a current in-depth analysis of data on real-world adherence to and persistence with LLT in Germany demonstrated a rate of treatment discontinuation of 50% after 36 months [66,67].”
BackgroundPuteri, M. U., Azmi, N. U., Kato, M., & Saputri, F. C. (2022) · Life · doi:10.3390/life12020190 · Cited by 39 · see citing works
Köenig, W., Conde, L. G., Landmesser, U., Leiter, L. A., Ray, K. K., Schwartz, G. G., Wright, R. S., Han, J., & Raal, F. J. (2022) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-022-07413-0 · Cited by 37 · cited 1× · see citing works
“ORION 9, 10, and 11 trials have proved inclisiran 284 mg has good tolerability and efficacy in long-term LDL-C reduction; PCSK9 plasma levels were reduced by about 80% in patients with a very high risk of cardiovascular disease [53].”
BackgroundMartinez, J.-M., Brunet, A., Hurbin, F., DiCioccio, A. T., Rauch, C., & Fabre, D. (2018) · Clinical Pharmacokinetics · doi:10.1007/s40262-018-0669-y · Cited by 33 · see citing works
Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis
Alannan, M., Fatrouni, H., Trézéguet, V., Dittrich-Domergue, F., Moreau, P., Siegfried, G., Liet, B., Khatib, A., Grosset, C. F., Badran, B. M., et al. (2022) · Cells · doi:10.3390/cells12010062 · Cited by 33 · cited 1× · see citing works
“), it can be especially valuable as a potential therapeutic target [30].”
BackgroundWu, M., Dong, B., Cao, A., Li, H., & Liu, J. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.08.012 · Cited by 32 · cited 1× · see citing works
“Similarly, higher postprandial insulin levels promote PCSK9 mRNA synthesis as a result of SREBP1 activation [3,4].”
BackgroundInternalized PCSK9 dissociates from recycling LDL receptors in PCSK9-resistant SV-589 fibroblasts
Nguyen, M.-A., Kosenko, T., & Lagace, T. A. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m044156 · Cited by 30 · cited 1× · see citing works
“Since the major part of LDL receptors is reused while PCSK9 prevents their recycling in cells, a monoclonal antibody block would promote LDLR recycling on cell membranes and induce LDL-C uptake from plasma and a decrease in circulating LDL-C [55].”
BackgroundEfficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update
Kaddoura, R., Orabi, B., & Salam, A. M. (2020) · Journal of Drug Assessment · doi:10.1080/21556660.2020.1801452 · Cited by 30 · cited 1× · see citing works
“This can be, at least partially, explained by the fact that the patients felt reassured due to substantial LDL-C reduction to recommended LDL-C levels even if the levels had been very high previously [65].”
BackgroundDjebli, N., Martinez, J.-M., Lohan, L., Khier, S., Brunet, A., Hurbin, F., & Fabre, D. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-016-0505-1 · Cited by 29 · cited 1× · see citing works
“Similar results were described for another inhibitor, alirocumab [58,59].”
ResultEstimation of the major cardiovascular events prevention with Inclisiran
Cordero, A., Santos‐Gallego, C. G., Fácila, L., Rodríguez‐Mañero, M., Bertomeu‐González, V., Castellano, J. M., Seijas‐Amigo, J., Núñez, J. E., Zuazola, P., González‐Juanatey, J. R., et al. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2020.09.021 · Cited by 29 · cited 2× · see citing works
“In general, new technologies based on gene editing are a potential for clinical applications in the future, including, in particular, PCSK9 targeting for hypercholesterolemia management [54].”
BackgroundMethodGrewal, T., & Buechler, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031070 · Cited by 27 · cited 1× · see citing works
“However, elevated PCSK9 levels can promote the production of cholesterol and triglycerides specific to enterocytes [19].”
BackgroundCicero, A. F. G., Tartagni, E., & Ertek, S. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.902929 · Cited by 26 · cited 1× · see citing works
“Again, in Phase II studies, AMG145 kinetics followed approximately linear profile at doses > 140 mg every 2 weeks, both when administered alone or with statins [57].”
BackgroundInclisiran: How Widely and When Should We Use It?
Pirillo, A., & Catapano, A. L. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01056-0 · Cited by 26 · cited 1× · see citing works
“This is why inclisiran can be used for CVD prevention [69].”
BackgroundSafety and Tolerability of PCSK9 Inhibitors: Current Insights
Kosmas, C. E., Skavdis, A., Sourlas, A., et al. (2020) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 26 · see citing works
Adaptive Immune Responses in Human Atherosclerosis
Lee, S., Bartlett, B., & Dwivedi, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239322 · Cited by 25 · cited 1× · see citing works
“PCSK9 stimulates VCAM-1 expression in vascular SMCs, while inhibition of PCSK9 in cultured vascular SMCs leads to a substantial reduction in VCAM-1 expression [36].”
BackgroundClinical Implications and Outcomes of the Orion Phase Iii Trials
Brandts, J., & Ray, K. K. (2020) · Future Cardiology · doi:10.2217/fca-2020-0150 · Cited by 24 · cited 1× · see citing works
“ORION trials have been studying inclisiran safety and efficacy in reducing LDL-C [72].”
BackgroundFaraj, M. (2020) · Journal of Biomedical Research · doi:10.7555/jbr.34.20190124 · Cited by 23 · cited 1× · see citing works
“Studies have shown that PCSK9 promotes hepatic and intestinal apoB-100 expression and reduces VLDLR levels in fat cells, resulting in LDLR-independent action of PCSK9 on cholesterol concentrations [18].”
BackgroundPelletier, R. ‐., Layeghkhavidaki, H., Seidah, N. G., Prat, A., & Vitale, M. L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.889972 · Cited by 15 · cited 1× · see citing works
“The activation of each of these pathways depends on the PCSK9 binding partner [12,13].”
BackgroundPCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity
Alannan, M., Seidah, N. G., & Merched, A. J. (2022) · Cells · doi:10.3390/cells11244132 · Cited by 14 · cited 1× · see citing works
“PCSK9 can influence lipid and lipoprotein concentrations in plasma not only through decreased lipoprotein uptake in the liver, but also by accelerating lipogenesis in the liver, which is regulated both by apoE and LDLR [17].”
BackgroundMoradi, A., Maleki, M., Ghaemmaghami, Z., Khajali, Z., Noohi, F., Moghadam, M. H., Kalyinia, S., Mowla, S. J., Seidah, N. G., & Malakootian, M. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.625959 · Cited by 14 · cited 1× · see citing works
“There have been identified over 250 mutations occurring in different PCSK9 domains [22].”
BackgroundA Systematic Approach to Assess the Activity and Classification of PCSK9 Variants
Uribe, K. B., Chemello, K., Larrea, A., Benito‐Vicente, A., Galicia-García, U., Bourane, S., Jaafar, A. K., Lambert, G. C., & Martı́n, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413602 · Cited by 14 · cited 1× · see citing works
“In contrast, PCSK9 KO mice demonstrate high hepatic LDLR expression and low plasma LDL-C concentrations [25].”
BackgroundEffect of PCSK9 Inhibitors on Hemostasis in Patients with Isolated Hypercholesterolemia
Basiak, M., Hachuła, M., Kosowski, M., & Okopień, B. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11092542 · Cited by 14 · see citing works
Association between the rs615563 variant of PCSK9 gene and circulating lipids and Type 2 diabetes
Jazdani, S. T., Shahbazian, H. B., Cheraghian, B., Jalali, M. T., & Mohammadtaghvaei, N. (2021) · BMC Research Notes · doi:10.1186/s13104-021-05723-4 · Cited by 2 · see citing works
Statin escape phenomenon: Fact or fiction?
Barkas, F., Elisaf, M., Klouras, E., Dimitriou, T., Tentolouris, N., & Liberopoulos, E. N. (2017) · World Journal of Experimental Medicine · doi:10.5493/wjem.v7.i1.25 · Cited by 1 · cited 1× · see citing works
“This is a potential mechanism of limitation of the efficacy of statin-induced LDL-C reduction, which can explain the “6% rule for statins”, which states that the doubling of a statin dose brings only approximately 6% additional reduction in LDL-C level [49,50].”
Background
Flagged first, then by citations
1 of the 78 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Sympathetic Nervous System and Atherosclerosis
Wang, Y., Anesi, J., Maier, M. C., Myers, M. A., Oqueli, E., Sobey, C. G., Drummond, G. R., & Denton, K. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713132 · Cited by 41 · see citing works
Giglio, R. V., Muzurović, E. M., Patti, A. M., Toth, P. P., Agarwal, M. A., Almahmeed, W. A., Klisic, A. N., Ciaccio, M., & Rizzo, M. (2023) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/10742484231186855 · Cited by 11 · see citing works
“35,36 PCSK9 has the ability to bind to Toll-like receptors, thus mediating the in fl ammatory response, and to bind to class B scavenger receptors/CD36, thus accelerating platelet activation and thrombosis.”
BackgroundInfluentialInnovative mRNA Vaccine Approaches in Targeting Atherosclerosis: A New Era in Cardiovascular Therapy
Kumar, R., Krishnaperumal, G., & Vellapandian, C. (2024) · Cureus · doi:10.7759/cureus.74141 · Cited by 9 · see citing works
Satyam, S. M., El-Tanani, M., Patni, M. A., Rehman, A., Irshad, S. M., Raheem, R., Junais, E., John, A. A., Rassal, R. Y., Kumari, R., et al. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-05515-3 · Cited by 5 · see citing works
“Through its application of RNA interference (RNAi) technology Inclisiran targets messenger RNA (mRNA) of pro-protein convertase subtilisin/kexin type 9 (PCSK9) within hepatocytes to decrease PCSK9 synthesis at the transcriptional level [64, 65].”
Desouky, M. A., El‐Magd, M. A., Mousa, M. A., Mallick, A. H., Khan, D., & Desouky, D. A. (2025) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-025-00694-y · Cited by 4 · see citing works
“Examining how PCSK9 interacts with other inflammatory pathways, such the NLRP3 inflammasome, which is crucial for atherosclerosis, is one potential field [211].”
Desouky, D. A., Nosair, N. A. E.-A., Salama, M. K., El‐Magd, M. A., Desouky, M. A., & Sherief, D. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05154-2 · Cited by 4 · see citing works
“Statin therapy is the most widely used therapeutic approach for atherosclerosis; nonetheless, it has some drawbacks, such as adverse effects and poor compliance [12].”
Therapeutic approach in the treatment of dyslipidemia: Novelties and challenges
Lalic, K. S., Rajkovic, N., Popović, L., Lukač, S. S., Rasulić, I., Petakov, A., Krstic, M., & Mitrović, M. (2024) · Galenika Medical Journal · doi:10.5937/galmed2409031l · Cited by 2 · see citing works
Treatment of dyslipidemia: PCSK-9 in focus
Lukač, S. S., Popović, L., Rasulić, I., Petakov, A., Bogdanović, J. M., Mitrović, M., Krstic, M., & Lalic, K. S. (2025) · Medicinska istrazivanja · doi:10.5937/medi0-55356
- Authors
- Poznyak, A. V., Sukhorukov, V. N., Eremin, I. I., Nadelyaeva, I. I., Gutyrchik, N. A., & Orekhov, A. N.
- Affiliations
- Institute for Atherosclerosis Research (RU)
- Research Institute of General Pathology and Pathophysiology, the Russian Academy of Medical Sciences (RU)
- Russian Scientific Center of Surgery (RU)
- Corresponding author
- Poznyak, Anastasia V.
- Orekhov, Alexander N.
- ORCID
- Venue
- Biomedicines
- Publisher
- MDPI AG
- Published
- 2023-02-09
- Volume
- 11
- Issue
- 2
- Pages
- 503
- ISSN
- 2227-9059 (ISSN-L)
- PMC
- PMC9953442
- OpenAlex
- W4319985924
- Semantic Scholar
- 9e39b6a16ec17a1e9513e444a5da139dfef613c6
- Cited by
- 8
- References
- 78
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicines (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Russian Science Foundation (22-65-00005)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- PCSK9, atherosclerosis, lipid metabolism, atherogenesis, statin therapy, PCSK9 inhibitors, cardiovascular disease, hypercholesterolemia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
