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The fibrous cap: a promising target in the pharmacotherapy of atherosclerosis

Stanislav Yanev, Maria Zhelyazkova-Savova, George N. Chaldakov

Abstract

Recent advances have shed light on the relationship between smooth muscle cell (SMC) phenotypic modulation, resolution of inflammation and atherosclerotic plaque stability. The thick fibrous cap covering the lipid core of plaques is composed of bundles of SMC and collagen fibers and few macrophages and lymphocytes, all of which make the plaque resistant to rupture. The thin fibrous cap contains many macrophages and lymphocytes, few SMC and less collagen fibers, all of which may weaken the cap, leaving the plaque vulnerable to rupture. In the present Dance Round, we, at a pharmacotherapeutic level, address the possibility of how the control over the activity of the essential cellular components of the plaque, particularly its fibrous cap, could be implicated in plaque stabilization, focusing on (i) the modulation of SMC from contractile to secretory (fibrogenic) phenotype, (ii) the control on plaque inflammation-resolution processes, and (iii) the reduction of plaque lipid content. Further studies on both unstable plaque and aortic aneurysm, which share a similar, matrix-based vulnerability, may bring new insights for pharmacotherapy of vascular injuries.

Keywords

atherosclerotic plaque, fibrous cap, smooth muscle cells, collagen, phenotypic modulation, macrophages, matrix metalloproteinases, pro-resolving mediators, acetylcholine, nerve growth factor

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References

Ghenev PI, Aloe L, Kisheva AR, Singh M, Panayotov P, Fiore M, et al. QUO VADIS, ATHEROGENESIS? Part 1. Smooth muscle cell secretion – how foe becomes friend in the fight against the atherosclerotic plaque. Biomed Rev 2017; 28:134-138.

Chaldakov GN. George E. Palade lecture. Human body as a multicrine system, with special reference to cell protein secretion: From vascular smooth muscles to adipose tissue. Biomed Rev 2016; 27(VIII - XIX.

Yanev S, Fiore M, Hinev A, Ghenev PI, Hristova MG, Panayotov P, et al. From antitubulins to trackins. Biomed Rev 2016; 27:59-67.

Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med 1999; 340(2): 115-126. [DOI: 10.1056/NEJM199901143400207]

Chaldakov GN. Antitubulins - a new therapeutic approach for atherosclerosis? Atherosclerosis 1982; 44(3): 385-390.[DOI: 10.1016/0021-9150(82)90013-2]

Chaldakov GN, Vankov VN. Morphological aspects of secretion in the arterial smooth muscle cell, with special reference to the Golgi complex and microtubular cytoskeleton. Atherosclerosis 1986; 61(3): 175-192. [DOI: 10.1016/0021-9150(86)90137-1]

Lafont A, Libby P. The smooth muscle cell: sinner or saint in restenosis and the acute coronary syndromes? J Am Coll Cardiol 1998; 32(1): 283-285. [DOI: https://doi. org/10.1016/S0735-1097(98)00216-2]

Schwartz SM, Virmani R, Rosenfeld ME. The good smooth muscle cells in atherosclerosis. Curr Atheroscler Rep 2000; 2(5): 422-429. [DOI: 10.1007/s11883-000-0081-5]

Dave T, Ezhilan J, Vasnawala H, Somani V. Plaque regres-sion and plaque stabilisation in cardiovascular diseases. Indian J Endocrinol Metab 2013; 17(6): 983-989. [DOI: 10.4103/2230-8210.122604]

Daida H, Dohi T, Fukushima Y, Ohmura H, Miyauchi K. The Goal of Achieving Atherosclerotic Plaque Regression with Lipid-Lowering Therapy: Insights from IVUS Trials. J Atheroscler Thromb 2019; 26(592-600. [DOI: 10.5551/jat.48603]

Guan S, Zhang Y, Wang B, Li W. Medical Therapy Induced Regression of Plaque in a Female Patient with ASCVD. Int Heart J 2019; 60(1): 175-177. [DOI: 10.1536/ihj.17-394]

Chaldakov GN. Colchicine, a microtubule-disassembling drug, in the therapy of cardiovascular diseases. Cell Biol Int 2018; 42(8): 1079-1084. [DOI: 10.1002/cbin.10988]

Chaldakov GN, Fiore M, Ghenev PI, Stankulov IS, Angelucci F, Pavlov PS, et al. Conceptual novelities in atherogenesis: smooth muscle cells,adventitia, and adipose tissue. Biomed Rev 2000; 11:63-67.

Rabbani R, Topol EJ. Strategies to achieve coronary ar-terial plaque stabilization. Cardiovasc Res 1999; 41(2):402-417. [DOI: 10.1016/s0008-6363(98)00279-x]

Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabi-lization: mechanisms, models, and therapeutic strategies. Circ Res 2014; 114(1): 214-226. [DOI: 10.1161/CIRCRE-SAHA.114.302355]

Takata K, Imaizumi S, Zhang B, Miura S-I, Saku K. Sta-bilization of high-risk plaques. Cardiovasc Diagn Ther 2016; 6(4): 304-321. [DOI: 10.21037/cdt.2015.10.03]

Ylä-Herttuala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Herrmann J, et al. Stabilization of athero-sclerotic plaques: an update. Eur Heart J 2013; 34(42): 3251-3258. [DOI:10.1093/eurheartj/eht301]

Chen P-Y, Qin L, Li G, Tellides G, Simons M. Smooth muscle FGF/TGFβ cross talk regulates atherosclerosis progression. EMBO Mol Med 2016; 8(7): 712-728. [DOI: 10.15252/emmm.201506181]

Dong M, Zhong L, Chen WQ, Ji XP, Zhang M, Zhao YX, et al. Doxycycline stabilizes vulnerable plaque via inhib-iting matrix metalloproteinases and attenuating inflam-mation in rabbits. PloS one 2012; 7(6): e39695-e39695.[DOI: 10.1371/journal.pone.0039695]

Xiong W, Knispel RA, Dietz HC, Ramirez F, Baxter BT. Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J Vasc Surg 2008; 47(1): 166-172; discussion 172. [DOI: 10.1016/j.jvs.2007.09.016]

Parker SJ, Stotland A, MacFarlane E, Wilson N, Orosco A, Venkatraman V, et al. Proteomics reveals Rictor as a noncanonical TGF-β signaling target during aneurysm progression in Marfan mice. Am J Physiol Heart Circ Physiol 2018; 315(5): H1112-H1126. [DOI: 10.1152/ajpheart.00089.2018]

Crosas-Molist E, Meirelles T, López-Luque J, Serra-Peina-do C, Selva J, Caja L, et al. Vascular Smooth Muscle Cell Phenotypic Changes in Patients With Marfan Syndrome. Arteriosc Thromb Vasc Biol 2015; 35(4): 960-972. [DOI: doi:10.1161/ATVBAHA.114.304412]

Hibender S, Franken R, Roomen Cv, Braake At, Made Ivd, Schermer EE, et al. Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model. Arteriosc Thromb Vasc Biol 2016; 36(8): 1618-1626. [DOI: doi:10.1161/ATVBAHA.116.307841]

Molloy KJ, Thompson MM, Jones JL, Schwalbe EC, Bell PR, Naylor AR, et al. Unstable carotid plaques exhibit raised matrix metalloproteinase-8 activity. Circulation 2004; 110(3): 337-343. [DOI: 10.1161/01. CIR.0000135588.65188.14]

Newby AC. Metalloproteinases and vulnerable athero-sclerotic plaques. Trends Cardiovasc Med 2007; 17(8):253-258. [DOI: 10.1016/j.tcm.2007.09.001]

Newby AC. Role of metalloproteinases in plaque rupture. Int J Gerontol 2007; 1(3): 103-111.

Ruddy JM, Ikonomidis JS, Jones JA. Multidimensional Contribution of Matrix Metalloproteinases to Athero-sclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability. J Vasc Res 2016; 53(1-2):1-16. [DOI: 10.1159/000446703]

Johnson JL, Devel L, Czarny B, George SJ, Jackson CL, Rogakos V, et al. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice. Arterioscler Thromb Vasc Biol 2011; 31(3): 528-535. [DOI: 10.1161/AT-VBAHA.110.219147]

Fredman G, Tabas I. Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 2017; 187(6): 1211-1221. [DOI: 10.1016/j. ajpath.2017.01.018]

Fredman G. Can Inflammation-Resolution Provide Clues to Treat Patients According to Their Plaque Pheno-type? Front Pharmacol 2019; 10(205). [DOI: 10.3389/fphar.2019.00205]

Carracedo M, Artiach G, Arnardottir H, Bäck M. The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification. Semin Immunopathol 2019; 41(6): 757-766.[DOI: 10.1007/s00281-019-00767-y]

Viola JR, Lemnitzer P, Jansen Y, Csaba G, Winter C, Neideck C, et al. Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice. Circ Res 2016; 119(9): 1030-1038. [DOI: doi:10.1161/CIRCRESAHA.116.309492]

Rosas-Ballina M, Tracey KJ. Cholinergic control of inflammation. J Intern Med 2009; 265(6): 663-679. [DOI: 10.1111/j.1365-2796.2009.02098.x]

Jhang J-F, Wang H-J, Hsu Y-H, Birder LA, Kuo H-C. Upregulation of neurotrophins and transforming growth factor-β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine-associated cystitis. Neurourol Urodyn 2019; 38(8): 2303-2310. [DOI: 10.1002/nau.24139]

Liu Z, Cao Y, Liu G, Yin S, Ma J, Liu J, et al. p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Exp Cell Res 2019; 383(1): 111504. [DOI: https://doi. org/10.1016/j.yexcr.2019.111504]

Rocco ML, Soligo M, Manni L, Aloe L. Nerve Growth Factor: Early Studies and Recent Clinical Trials. Curr Neuropharmacol 2018; 16(10): 1455-1465. [DOI: 10.21 74/1570159X16666180412092859]

Aloe L: Nerve growth factor, human skin ulcers and vascularization. Our experience. In: Progress in Brain Research. Volume 146: Elsevier, 2004; 515-522.

Aloe L, Tirassa P, Lambiase A. The topical application of nerve growth factor as a pharmacological tool for human corneal and skin ulcers. Pharmacol Res 2008; 57(4): 253-258. [DOI: https://doi.org/10.1016/j.phrs.2008.01.010]

Chaldakov GN, Fiore M, Stankulov IS, Manni L, Hris-tova MG, Antonelli A, et al.: Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease? In: Progress in Brain Research. Volume 146: Elsevier, 2004;279-289.

Li H, Zhang L, Yin D, Zhang Y, Miao J. Targeting Phos-phatidylcholine-Specific Phospholipase C for Atherogen-esis Therapy. Trends Cardiovasc Med 2010; 20(5): 172-176. [DOI: https://doi.org/10.1016/j.tcm.2011.02.002]

Zhang L, Zhao J, Su L, Huang B, Wang L, Su H, et al. D609 inhibits progression of preexisting atheroma and promotes lesion stability in apolipoprotein e-/- mice: a role of phosphatidylcholine-specific phospholipase in atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30(3): 411-418. [DOI: 10.1161/ATVBAHA.109.195768]

Zhao Y, Li K, Zhao B, Su L. Discovery of novel PC-PLC activity inhibitors. Chem Biol Drug Des 2019; 94(8. [DOI: 10.1111/cbdd.13606]

Meng A, Luberto C, Meier P, Bai A, Yang X, Hannun YA, et al. Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res 2004; 292(2): 385-392. [DOI: 10.1016/j.yexcr.2003.10.001]

Li Y, Huang T, Lou B, Ye D, Qi X, Li X, et al. Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor. Eur J Med Chem 2019; 163(864-882. [DOI: https://doi.org/10.1016/j. ejmech.2018.12.028]

Kühnast S, van der Hoorn JWA, Pieterman EJ, van den Hoek AM, Sasiela WJ, Gusarova V, et al. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res 2014; 55(10): 2103-2112. [DOI: 10.1194/jlr.M051326]

Hafiane A. Vulnerable Plaque, Characteristics, Detection, and Potential Therapies. J Cardiovasc Dev Dis 2019; 6(3): 26. [DOI: 10.3390/jcdd6030026]

Tang J, Lobatto ME, Hassing L, van der Staay S, van Rijs SM, Calcagno C, et al. Inhibiting macrophage prolifera-tion suppresses atherosclerotic plaque inflammation. Sci Adv 2015; 1(3). [DOI: 10.1126/sciadv.1400223]




DOI: http://dx.doi.org/10.14748/bmr.v30.6394

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About The Authors

Stanislav Yanev
Institute of Neurobiology, Department of Drug Toxicology, Bulgarian Academy of Sciences, Sofia
Bulgaria

Maria Zhelyazkova-Savova
Medical University of Varna
Bulgaria

Department of Pharmacology and Clinical Pharmacology and Therapeutics

George N. Chaldakov
Medical University of Varna
Bulgaria

Department of Anatomy and Cell Biology,

Institute for Advanced Study, Varna, Bulgaria

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