Novel Approaches to Anti-atherosclerotic Therapy: Cell-based Models and Herbal Preparations (Review of Our Own Data)

Author(s): Alexander N. Orekhov*, Andrey V. Grechko, Elena B. Romanenko, Dongwei Zhang, Dimitry A. Chistiakov

Journal Name: Current Drug Discovery Technologies

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Atherosclerosis is a chronic arterial disease characterized by vascular inflammation, accumulation of lipids in the arterial wall, and formation and growth of atherosclerotic plaques followed by ischemia. In subclinical atherosclerosis, cholesterol retention in subendothelial cells leads to induction of local inflammation, generation of foam cells and lesion formation, followed by a chain of other pathogenic events. Atherosclerotic progression can frequently be fatal, since plaque rupture may lead to thrombosis and acute events, such as myocardial infarction, stroke and sudden death. Traditional anti-atherosclerotic therapy is mainly focused on improving the blood lipid profile and does not target various stages of plaque progression. Obviously, treating the disease at initial stages is better than beginning treatment at advanced stages and, in that regard, current atherosclerosis management can be improved. Cholesterol retention is an important component of atherogenesis that precedes plaque formation. Therapeutic targeting of cholesterol retention may be beneficial for preventing further atherogenic progression. For this purpose, we suggest using herbal preparations due to good tolerability and suitability for long-lasting treatment. We developed test systems based on cultured human intimal aortic cells for rapid screening of potential anti-atherogenic drugs. With the help of these test systems, we selected several natural substances with significant anti-atherogenic activity and further use these compounds to prepare herbal preparations for anti-atherosclerotic therapy. These preparations were clinically tested and showed good safety and a potent anti-atherogenic potential.

Keywords: Cholesterol retention modified LDL, atherogenicity, cell-based test models, herbal drugs, anti-atherosclerotic therapy.

[1]
Orekhov A, Ivanova E. Introduction of the special issue Atherosclerosis and Related Diseases. Vessel Plus 2017; 1: 163-5.
[2]
Finking G, Hanke H. Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed rabbit as a model for atherosclerosis research. Atherosclerosis 1997; 135(1): 1-7.
[http://dx.doi.org/10.1016/S0021-9150(97)00161-5] [PMID: 9395267]
[3]
Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2012; 32(12): 2813-20.
[http://dx.doi.org/10.1161/ATVBAHA.112.300133] [PMID: 23152494]
[4]
Alipov V, Sukhorukov V, Karagodin V, Grechko A, Orekhov A. Chemical composition of circulating native and desialylated low density lipoprotein: What is the difference? Vessel Plus 2017; 1: 107-15.
[http://dx.doi.org/10.20517/2574-1209.2017.20]
[5]
Sobenin I, Galitsyna E, Grechko A, Orekhov A. Small dense and desialylated low density lipoprotein in diabetic patients. Vessel Plus 2017; 1: 29-37.
[http://dx.doi.org/10.20517/2574-1209.2016.12]
[6]
Harangi M, Szentpéteri A, Nádró B, et al. HDL subfraction distribution and HDL function in untreated dyslipidemic patients. Vessel Plus 2017; 1: 166-73.
[http://dx.doi.org/10.20517/2574-1209.2017.27]
[7]
Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116(16): 1832-44.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.676890] [PMID: 17938300]
[8]
Gustafsson M, Borén J. Mechanism of lipoprotein retention by the extracellular matrix. Curr Opin Lipidol 2004; 15(5): 505-14.
[http://dx.doi.org/10.1097/00041433-200410000-00003] [PMID: 15361785]
[9]
Proctor SD, Vine DF, Mamo JC. Arterial retention of apolipoprotein B(48)- and B(100)-containing lipoproteins in atherogenesis. Curr Opin Lipidol 2002; 13(5): 461-70.
[http://dx.doi.org/10.1097/00041433-200210000-00001] [PMID: 12352009]
[10]
Nikiforov N, Galstyan K, Nedosugova L, Elizova N, Kolmychkova K, Ivanova E. Proinflammatory monocyte polarization in type 2 diabetes mellitus and coronary heart disease Vessel Plus 2017; 1: 0.
[http://dx.doi.org/10.20517/2574-1209.2017.21]
[11]
Dubland JA, Francis GA. So Much Cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation. Curr Opin Lipidol 2016; 27(2): 155-61.
[http://dx.doi.org/10.1097/MOL.0000000000000279] [PMID: 26836481]
[12]
Gimbrone MA Jr, García-Cardeña G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol 2013; 22(1): 9-15.
[http://dx.doi.org/10.1016/j.carpath.2012.06.006] [PMID: 22818581]
[13]
Steyers CM III, Miller FJ Jr. Endothelial dysfunction in chronic inflammatory diseases. Int J Mol Sci 2014; 15(7): 11324-49.
[http://dx.doi.org/10.3390/ijms150711324] [PMID: 24968272]
[14]
Magalhaes A, Matias I, Palmela I, Brito MA, Dias S. LDL-cholesterol increases the transcytosis of molecules through endothelial monolayers. PLoS One 2016; 11(10) e0163988
[http://dx.doi.org/10.1371/journal.pone.0163988] [PMID: 27695052]
[15]
Alexander JJ, Miguel R, Piotrowski JJ. The effect of nifedipine on lipid and monocyte infiltration of the subendothelial space. J Vasc Surg 1993; 17(5): 841-7.
[http://dx.doi.org/10.1016/0741-5214(93)90033-I] [PMID: 8487352]
[16]
Orekhov AN, Kalenich OS, Tertov VV, Novikov ID. Lipoprotein immune complexes as markers of atherosclerosis. Int J Tissue React 1991; 13(5): 233-6.
[PMID: 1806545]
[17]
Jaakkola O, Solakivi T, Tertov VV, Orekhov AN, Miettinen TA, Nikkari T. Characteristics of low-density lipoprotein subfractions from patients with coronary artery disease. Coron Artery Dis 1993; 4(4): 379-85.
[http://dx.doi.org/10.1097/00019501-199304000-00010] [PMID: 8261211]
[18]
Kacharava AG, Tertov VV, Orekhov AN. Autoantibodies against low-density lipoprotein and atherogenic potential of blood. Ann Med 1993; 25(6): 551-5.
[http://dx.doi.org/10.1080/07853890.1993.12088583] [PMID: 8292305]
[19]
Tertov VV, Orekhov AN. Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima. Exp Mol Pathol 1997; 64(3): 127-45.
[http://dx.doi.org/10.1006/exmp.1997.2216] [PMID: 9439479]
[20]
Orekhov AN, Sobenin IA, Revin VV, Bobryshev YV. Development of antiatherosclerotic drugs on the basis of natural products using cell model approach. Oxid Med Cell Longev 2015; 2015 463797
[http://dx.doi.org/10.1155/2015/463797] [PMID: 26347804]
[21]
Orekhov AN, Tertov VV, Mukhin DN, Mikhailenko IA. Modification of low density lipoprotein by desialylation causes lipid accumulation in cultured cells: discovery of desialylated lipoprotein with altered cellular metabolism in the blood of atherosclerotic patients. Biochem Biophys Res Commun 1989; 162(1): 206-11.
[http://dx.doi.org/10.1016/0006-291X(89)91982-7] [PMID: 2751649]
[22]
Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Orekhov AN. Lipoprotein aggregation as an essential condition of intracellular lipid accumulation caused by modified low density lipoproteins. Biochem Biophys Res Commun 1989; 163(1): 489-94.
[http://dx.doi.org/10.1016/0006-291X(89)92163-3] [PMID: 2775281]
[23]
Tertov VV, Sobenin IA, Tonevitsky AG, Orekhov AN, Smirnov VN. Isolation of atherogenic modified (desialylated) low density lipoprotein from blood of atherosclerotic patients: separation from native lipoprotein by affinity chromatography. Biochem Biophys Res Commun 1990; 167(3): 1122-7.
[http://dx.doi.org/10.1016/0006-291X(90)90639-5] [PMID: 2322261]
[24]
Tertov VV, Sobenin IA, Orekhov AN. Similarity between naturally occurring modified desialylated, electronegative and aortic low density lipoprotein. Free Radic Res 1996; 25(4): 313-9.
[http://dx.doi.org/10.3109/10715769609149054] [PMID: 8889495]
[25]
Tertov VV, Kaplun VV, Sobenin IA, Boytsova EY, Bovin NV, Orekhov AN. Human plasma trans-sialidase causes atherogenic modification of low density lipoprotein. Atherosclerosis 2001; 159(1): 103-15.
[http://dx.doi.org/10.1016/S0021-9150(01)00498-1] [PMID: 11689212]
[26]
Tertov VV, Nikonova EY, Nifant’ev NE, Bovin NV, Orekhov AN. Human plasma trans-sialidase donor and acceptor specificity. Biochemistry (Mosc) 2002; 67(8): 908-13.
[http://dx.doi.org/10.1023/A:1019918704920] [PMID: 12223090]
[27]
Nikonova EY, Tertov VV, Sato C, Kitajima K, Bovin NV. Specificity of human trans-sialidase as probed with gangliosides. Bioorg Med Chem Lett 2004; 14(20): 5161-4.
[http://dx.doi.org/10.1016/j.bmcl.2004.07.058] [PMID: 15380219]
[28]
Higuchi MdeL. Reis MM, Sambiase NV, et al Coinfection with Mycoplasma pneumoniae and Chlamydia pneumoniae in ruptured plaques associated with acute myocardial infarction Arq Bras Cardiol 2003; 81(1): 12-22, 1-11
[http://dx.doi.org/10.1590/S0066-782X2003000900001] [PMID: 12908069]
[29]
Momiyama Y, Ohmori R, Taniguchi H, Nakamura H, Ohsuzu F. Association of Mycoplasma pneumoniae infection with coronary artery disease and its interaction with chlamydial infection. Atherosclerosis 2004; 176(1): 139-44.
[http://dx.doi.org/10.1016/j.atherosclerosis.2004.04.019] [PMID: 15306186]
[30]
Garavelo SM, Higuchi ML, Pereira JJ, et al. Comparison of the protective effects of individual components of particulated trans-Sialidase (PTCTS), PTC and TS, Against High Cholesterol Diet-Induced Atherosclerosis in Rabbits. BioMed Res Int 2017; 20177212985
[http://dx.doi.org/10.1155/2017/7212985] [PMID: 28337456]
[31]
Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982; 23(1): 97-104.
[PMID: 7057116]
[32]
Avogaro P, Bon GB, Cazzolato G. Presence of a modified low density lipoprotein in humans. Arteriosclerosis 1988; 8(1): 79-87.
[http://dx.doi.org/10.1161/01.ATV.8.1.79] [PMID: 3341993]
[33]
Tertov VV, Bittolo-Bon G, Sobenin IA, Cazzolato G, Orekhov AN, Avogaro P. Naturally occurring modified low density lipoproteins are similar if not identical: more electronegative and desialylated lipoprotein subfractions. Exp Mol Pathol 1995; 62(3): 166-72.
[http://dx.doi.org/10.1006/exmp.1995.1018] [PMID: 8612720]
[34]
Orekhov AN, Tertov VV, Mukhin DN. Desialylated low density lipoprotein--naturally occurring modified lipoprotein with atherogenic potency. Atherosclerosis 1991; 86(2-3): 153-61.
[http://dx.doi.org/10.1016/0021-9150(91)90211-K] [PMID: 1872910]
[35]
Tertov VV, Sobenin IA, Orekhov AN, Jaakkola O, Solakivi T, Nikkari T. Characteristics of low density lipoprotein isolated from circulating immune complexes. Atherosclerosis 1996; 122(2): 191-9.
[http://dx.doi.org/10.1016/0021-9150(95)05737-4] [PMID: 8769682]
[36]
La Belle M, Krauss RM. Differences in carbohydrate content of low density lipoproteins associated with low density lipoprotein subclass patterns. J Lipid Res 1990; 31(9): 1577-88.
[PMID: 2246611]
[37]
Orekhov AN, Bobryshev YV, Sobenin IA, Melnichenko AA, Chistiakov DA. Modified low density lipoprotein and lipoprotein-containing circulating immune complexes as diagnostic and prognostic biomarkers of atherosclerosis and type 1 diabetes macrovascular disease. Int J Mol Sci 2014; 15(7): 12807-41.
[http://dx.doi.org/10.3390/ijms150712807] [PMID: 25050779]
[38]
Gratchev A, Sobenin I, Orekhov A, Kzhyshkowska J. Monocytes as a diagnostic marker of cardiovascular diseases. Immunobiology 2012; 217(5): 476-82.
[http://dx.doi.org/10.1016/j.imbio.2012.01.008] [PMID: 22325375]
[39]
Orekhov AN, Kosykh VA, Repin VS, Smirnov VN. Cell proliferation in normal and atherosclerotic human aorta. I. Flow cytofluorometric determination of cellular deoxyribonucleic acid content. Lab Invest 1983; 48(4): 395-8.
[PMID: 6834785]
[40]
Maldonado A, Game BA, Song L, Huang Y. Up-regulation of matrix metalloproteinase-1 expression in U937 cells by low-density lipoprotein-containing immune complexes requires the activator protein-1 and the Ets motifs in the distal and the proximal promoter regions. Immunology 2003; 109(4): 572-9.
[http://dx.doi.org/10.1046/j.1365-2567.2003.01694.x] [PMID: 12871225]
[41]
Chazov EI, Tertov VV, Orekhov AN, et al. Atherogenicity of blood serum from patients with coronary heart disease. Lancet 1986; 2(8507): 595-8.
[http://dx.doi.org/10.1016/S0140-6736(86)92426-8] [PMID: 2875319]
[42]
Orekhov AN, Tertov VV, Novikov ID, et al. Lipids in cells of atherosclerotic and uninvolved human aorta. I. Lipid composition of aortic tissue and enzyme-isolated and cultured cells. Exp Mol Pathol 1985; 42(1): 117-37.
[http://dx.doi.org/10.1016/0014-4800(85)90022-X] [PMID: 3967748]
[43]
Orekhov AN, Tertov VV, Kudryashov SA, Khashimov KhA, Smirnov VN. Primary culture of human aortic intima cells as a model for testing antiatherosclerotic drugs. Effects of cyclic AMP, prostaglandins, calcium antagonists, antioxidants, and lipid-lowering agents. Atherosclerosis 1986; 60(2): 101-10.
[http://dx.doi.org/10.1016/0021-9150(86)90002-X] [PMID: 3013216]
[44]
Corsini A, Grignaffini P, Beitz J, et al. Effect of trapidil derivative AR 12456 on intracellular cholesterol homeostasis in human hepatoma cell line Hep G2. Cytotechnology 1993; 11: S15-7.
[http://dx.doi.org/10.1007/BF00746043]
[45]
Lesnik P, Dachet C, Petit L, et al. Impact of a combination of a calcium antagonist and a beta-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and efflux of cholesterol in human macrophages and murine J774 cells. Arterioscler Thromb Vasc Biol 1997; 17(5): 979-88.
[http://dx.doi.org/10.1161/01.ATV.17.5.979] [PMID: 9157964]
[46]
Orekhov AN, Misharin AYu , Tertov VV, et al. Artificial HDL as an anti-atherosclerotic drug. Lancet 1984; 2(8412): 1149-50.
[http://dx.doi.org/10.1016/S0140-6736(84)91574-5] [PMID: 6150198]
[47]
Tertov VV, Panosyan AG, Akopov SE, Orekhov AN. The effects of eicozanoids and lipoxygenase inhibitors on the lipid metabolism of aortic cells. Biomed Biochim Acta 1988; 47(10-11): S286-8.
[PMID: 3150271]
[48]
Giessler C, Fahr A, Tertov VV, et al. Trapidil derivatives as potential antiatherosclerotic drugs. Arzneimittelforschung 1987; 37(5): 538-41.
[PMID: 3040019]
[49]
Orekhov AN, Baldenkov GN, Tertov VV, et al. Cardiovascular drugs and atherosclerosis: effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells. J Cardiovasc Pharmacol 1988; 12(Suppl. 6): S66-8.
[http://dx.doi.org/10.1097/00005344-198812006-00017] [PMID: 2468911]
[50]
Sobenin IA, Maksumova MA, Slavina ES, Balabolkin MI, Orekhov AN. Sulfonylureas induce cholesterol accumulation in cultured human intimal cells and macrophages. Atherosclerosis 1994; 105(2): 159-63.
[http://dx.doi.org/10.1016/0021-9150(94)90045-0] [PMID: 8003091]
[51]
Orekhov AN, Ivanova EA. Cellular models of atherosclerosis and their implication for testing natural substances with anti-atherosclerotic potential. Phytomedicine 2016; 23(11): 1190-7.
[http://dx.doi.org/10.1016/j.phymed.2016.01.003] [PMID: 26922038]
[52]
Orekhov AN, Tertov VV, Sobenin IA, Pivovarova EM. Direct anti-atherosclerosis-related effects of garlic. Ann Med 1995; 27(1): 63-5.
[http://dx.doi.org/10.3109/07853899509031938] [PMID: 7742001]
[53]
Orekhov AN, Sobenin IA, Korneev NV, et al. Anti-atherosclerotic therapy based on botanicals. Recent Pat Cardiovasc Drug Discov 2013; 8(1): 56-66.
[http://dx.doi.org/10.2174/18722083113079990008] [PMID: 23176379]
[54]
Sobenin IA, Andrianova IV, Lakunin KY, Karagodin VP, Bobryshev YV, Orekhov AN. Anti-atherosclerotic effects of garlic preparation in freeze injury model of atherosclerosis in cholesterol-fed rabbits. Phytomedicine 2016; 23(11): 1235-9.
[http://dx.doi.org/10.1016/j.phymed.2015.10.014] [PMID: 26739249]
[55]
Salonen R, Nyyssönen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995; 92(7): 1758-64.
[http://dx.doi.org/10.1161/01.CIR.92.7.1758] [PMID: 7671358]
[56]
Sobenin IA, Nedosugova LV, Filatova LV, Balabolkin MI, Gorchakova TV, Orekhov AN. Metabolic effects of time-released garlic powder tablets in type 2 diabetes mellitus: the results of double-blinded placebo-controlled study. Acta Diabetol 2008; 45(1): 1-6.
[http://dx.doi.org/10.1007/s00592-007-0011-x] [PMID: 17823766]
[57]
Sobenin IA, Andrianova IV, Demidova ON, Gorchakova T, Orekhov AN. Lipid-lowering effects of time-released garlic powder tablets in double-blinded placebo-controlled randomized study. J Atheroscler Thromb 2008; 15(6): 334-8.
[http://dx.doi.org/10.5551/jat.E550] [PMID: 19060427]
[58]
Sobenin IA, Pryanishnikov VV, Kunnova LM, Rabinovich YA, Martirosyan DM, Orekhov AN. The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients with coronary artery disease. Lipids Health Dis 2010; 9: 119.
[http://dx.doi.org/10.1186/1476-511X-9-119] [PMID: 20958974]
[59]
Sobenin IA, Chistiakov DA, Bobryshev YV, Orekhov AN. Blood atherogenicity as a target for anti-atherosclerotic therapy. Curr Pharm Des 2013; 19(33): 5954-62.
[http://dx.doi.org/10.2174/1381612811319330014] [PMID: 23438956]
[60]
Nikitina NA, Sobenin IA, Myasoedova VA, et al. Antiatherogenic effect of grape flavonoids in an ex vivo model. Bull Exp Biol Med 2006; 141(6): 712-5.
[http://dx.doi.org/10.1007/s10517-006-0260-7] [PMID: 17364057]
[61]
Murillo AG, Fernandez ML. The relevance of dietary polyphenols in cardiovascular protection. Curr Pharm Des 2017; 23(17): 2444-52.
[http://dx.doi.org/10.2174/1381612823666170329144307] [PMID: 28356040]
[62]
Sobenin IA, Myasoedova VA, Orekhov AN. Antiatherogenic action of isoflavonoid-rich botanicals: an implementation for atherosclerosis prevention in postmenopausal women. J Clin Lipidol 2007; 7: 491.
[63]
Sobenin I, Myasoedova V, Orekhov A. Atherosclerosis prevention in postmenopausal women with the isoflavonoid-rich dietary supplement Karinat. J Clin Lipidol 2008; 2: S26-7.
[http://dx.doi.org/10.1016/j.jacl.2008.08.059]
[64]
Myasoedova VA, Kirichenko TV, Melnichenko AA, et al. Anti-atherosclerotic effects of a phytoestrogen-rich herbal preparation in postmenopausal women. Int J Mol Sci 2016; 17(8)E1318
[http://dx.doi.org/10.3390/ijms17081318] [PMID: 27529226]
[65]
Gorchakova TV, Suprun IV, Sobenin IA, Orekhov AN. Use of natural products in anticytokine therapy. Bull Exp Biol Med 2007; 143(3): 316-9.
[http://dx.doi.org/10.1007/s10517-007-0099-6] [PMID: 18225751]
[66]
Gorchakova T, Myasoedova V, Sobenin I, Orekhov A. Atherosclerosis preventionwith the anti-inflammatory dietary supplement Inflaminat. Atheroscler Suppl 2009; 10: 387.
[http://dx.doi.org/10.1016/S1567-5688(09)70682-8]
[67]
Orekhov AN, Melnichenko AA, Sobenin IA. Approach to reduction of blood atherogenicity. Oxid Med Cell Longev 2014; 2014738679
[http://dx.doi.org/10.1155/2014/738679] [PMID: 25101152]
[68]
Myasoedova VA, Ivashinnikova GA, Sobenin IA, Ivanova EA, Orekhov AN. Blood serum atherogenicity: Cellular test for the development of anti-atherosclerotic therapy. Curr Pharm Des 2017; 23(8): 1195-206.
[http://dx.doi.org/10.2174/1381612823666170102121927] [PMID: 28042768]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 3
Year: 2020
Published on: 15 July, 2020
Page: [278 - 285]
Pages: 8
DOI: 10.2174/1570163816666190101112241
Price: $65

Article Metrics

PDF: 21
HTML: 2