Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Effect of a Peptide Construct on Differentiated Macrophage MMP-2 and MMP-9 Levels of Varicose Patients

Author(s): Golnaz Esfandiari, Azim S. Biranvand, Adeleh Poursaleh, Naser Kakavandi, Fahimeh Fattahi, Ghasem Ghasempour, Elham Bahraini, Mohsen Khosravi and Mohammad Najafi*

Volume 25, Issue 40, 2019

Page: [4303 - 4309] Pages: 7

DOI: 10.2174/1381612825666191029105203

Price: $65

Abstract

Background: The Matrix Metalloproteinase (MMPs) secreted from macrophages can affect the extracellular matrix remodeling process and improve varicose veins.

Aim: The aim of this study was to investigate the MMP-2 and MMP-9 gene expression and activity levels in the differentiated macrophages M2 of subjects with varicose veins, and to evaluate a peptide construct on their catalytic functions.

Methods: The macrophages were differentiated from the monocytes using M-CSF. The MMP-2 and MMP-9 gene expression and activity levels were measured by RT-qPCR and Zymography techniques, respectively. A peptide construct (ESLCG) was predicted with bioinformatics tools, and was prepared for the study of enzyme functions as compared to Batimastat. Furthermore, the docking studies were obtained for the evaluation of interactions between peptide construct, Batimastat and enzyme 3D structures.

Results: The results showed significant increases in MMP2 and MMP9 gene expression levels (P<0.001 and P<0.004, respectively) and gelatinolytic activities (P<0.001 and P<0.0001, respectively) in the macrophages. In agreement with the inhibitory effects of Batimastat, the peptide construct inhibited the MMP-2 and MMP-9 gelatinolytic activities up to 6.8 and 6.5 folds in the concentration of 150 µM. The docking analyses showed that the Lys187, Arg98, Leu49, Gly189, Leu190, Met97, Tyr53 and Phe57 residues of MMP-2 and the Leu187, His190, Glu402, His401, His405 and His411 residues of MMP-9 are interacted with the atoms of Batimastat and ESLCG peptide.

Conclusion: The ESLCG peptide may be applied as an inhibitor of MMP-2 and MMP-9 enzymes in the subjects with varicose veins.

Keywords: MMP-2, MMP-9, varicose, macrophage, peptide construct, monocytes.

« Previous Next »
[1]
Robertson L, Evans C, Fowkes FG. Epidemiology of chronic venous disease. Phlebology 2008; 23(3): 103-11.
[http://dx.doi.org/10.1258/phleb.2007.007061] [PMID: 18467617]
[2]
Xiao Y, Huang Z, Yin H, Lin Y, Wang S. In vitro differences between smooth muscle cells derived from varicose veins and normal veins. J Vasc Surg 2009; 50(5): 1149-54.
[http://dx.doi.org/10.1016/j.jvs.2009.06.048] [PMID: 19703751]
[3]
Atta HM. Varicose veins: role of mechanotransduction of venous hypertension. Int J Vasc Med 2012; 2012: 1-13.
[http://dx.doi.org/10.1155/2012/538627]
[4]
van Groenendael L, van der Vliet JA, Flinkenflögel L, Roovers EA, van Sterkenburg SM, Reijnen MM. Treatment of recurrent varicose veins of the great saphenous vein by conventional surgery and endovenous laser ablation. J Vasc Surg 2009; 50(5): 1106-13.
[http://dx.doi.org/10.1016/j.jvs.2009.06.057] [PMID: 19878788]
[5]
Lim CS, Gohel MS, Shepherd AC, Paleolog E, Davies AH. Venous hypoxia: a poorly studied etiological factor of varicose veins. J Vasc Res 2011; 48(3): 185-94.
[http://dx.doi.org/10.1159/000320624] [PMID: 21099225]
[6]
Bergan JJ, Schmid-Schönbein GW, Coleridge Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. Minerva Cardioangiol 2007; 55(4): 459-76.
[PMID: 17653022]
[7]
Lu D, Kassab GS. Role of shear stress and stretch in vascular mechanobiology. J R Soc Interface 2011; 8(63): 1379-85.
[http://dx.doi.org/10.1098/rsif.2011.0177] [PMID: 21733876]
[8]
Labropoulos N, Tiongson J, Pryor L, et al. Definition of venous reflux in lower-extremity veins. J Vasc Surg 2003; 38(4): 793-8.
[http://dx.doi.org/10.1016/S0741-5214(03)00424-5] [PMID: 14560232]
[9]
Meissner MH, Moneta G, Burnand K, et al. The hemodynamics and diagnosis of venous disease. J Vasc Surg 2007; 46(6)(Suppl.): S4-S24.
[http://dx.doi.org/10.1016/j.jvs.2007.09.043] [PMID: 18068561]
[10]
Schmid-Schönbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology 2001; 52(1)(Suppl.): S27-34.
[http://dx.doi.org/10.1177/0003319701052001S04]
[11]
Kucukguven A, Khalil RA. Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets 2013; 14(3): 287-324.
[PMID: 23316963]
[12]
Meng X, Mavromatis K, Galis ZS. Mechanical stretching of human saphenous vein grafts induces expression and activation of matrix-degrading enzymes associated with vascular tissue injury and repair. Exp Mol Pathol 1999; 66(3): 227-37.
[http://dx.doi.org/10.1006/exmp.1999.2260] [PMID: 10486241]
[13]
Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology 2008; 23(2): 85-98.
[http://dx.doi.org/10.1258/phleb.2007.007027] [PMID: 18453484]
[14]
Kowalewski R, Sobolewski K, Wolanska M, Gacko M. Matrix metalloproteinases in the vein wall. Int Angiol 2004; 23(2): 164-9.
[PMID: 15507895]
[15]
Kosugi I, Urayama H, Kasashima F, Ohtake H, Watanabe Y. Matrix metalloproteinase-9 and urokinase-type plasminogen activator in varicose veins. Ann Vasc Surg 2003; 17(3): 234-8.
[http://dx.doi.org/10.1007/s10016-003-0005-2] [PMID: 12704537]
[16]
Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases progress in molecular biology and translational science 147. Prog Mol Biol Transl Sci 2017; 147: 1-73.
[17]
Reček C. Conception of the venous hemodynamics in the lower extremity. Angiology 2006; 57(5): 556-63.
[http://dx.doi.org/10.1177/0003319706293117] [PMID: 17067977]
[18]
Lim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg 2009; 96(11): 1231-42.
[http://dx.doi.org/10.1002/bjs.6798] [PMID: 19847861]
[19]
Lim CS, Kiriakidis S, Paleolog EM, Davies AH. Increased activation of the hypoxia-inducible factor pathway in varicose veins. J Vasc Surg 2012; 55(5): 1427-39.
[http://dx.doi.org/10.1016/j.jvs.2011.10.111]
[20]
Milkiewicz M, Doyle JL, Fudalewski T, Ispanovic E, Aghasi M, Haas TL. HIF-1α and HIF-2α play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle. J Physiol 2007; 583(Pt 2): 753-66.
[http://dx.doi.org/10.1113/jphysiol.2007.136325] [PMID: 17627993]
[21]
Jacob MP, Badier-Commander C, Fontaine V, Benazzoug Y, Feldman L, Michel JB. Extracellular matrix remodeling in the vascular wall. Pathol Biol (Paris) 2001; 49(4): 326-32.
[http://dx.doi.org/10.1016/S0369-8114(01)00151-1] [PMID: 11428168]
[22]
Saharay M, Shields DA, Georgiannos SN, Porter JB, Scurr JH, Coleridge Smith PD. Endothelial activation in patients with chronic venous disease. Eur J Vasc Endovasc Surg 1998; 15(4): 342-9.
[http://dx.doi.org/10.1016/S1078-5884(98)80039-7] [PMID: 9610348]
[23]
Lim CS, Qiao X, Reslan OM, et al. Prolonged mechanical stretch is associated with upregulation of hypoxia-inducible factors and reduced contraction in rat inferior vena cava. J Vasc Surg 2011; 53(3): 764-73.
[http://dx.doi.org/10.1016/j.jvs.2010.09.018] [PMID: 21106323]
[24]
Tomlinson ML, Garcia-Morales C, Abu-Elmagd M, Wheeler GN. Three matrix metalloproteinases are required in vivo for macrophage migration during embryonic development. Mech Dev 2008; 125(11-12): 1059-70.
[http://dx.doi.org/10.1016/j.mod.2008.07.005] [PMID: 18684398]
[25]
Raffetto JD, Qiao X, Koledova VV, Khalil RA. Prolonged increases in vein wall tension increase matrix metalloproteinases and decrease constriction in rat vena cava: potential implications in varicose veins. J Vasc Surg 2008; 48(2): 447-56.
[http://dx.doi.org/10.1016/j.jvs.2008.03.004] [PMID: 18502086]
[26]
Chen Y, Peng W, Raffetto JD, Khalil RA. Matrix metalloproteinases in remodeling of lower extremity veins and chronic venous disease Prog Mol Biol Trans Sci 2017; 147: 267-99.
[27]
Misra S, Fu AA, Rajan DK, et al. Expression of hypoxia inducible factor-1 α, macrophage migration inhibition factor, matrix metalloproteinase-2 and -9, and their inhibitors in hemodialysis grafts and arteriovenous fistulas. J Vasc Interv Radiol 2008; 19(2 Pt 1): 252-9.
[http://dx.doi.org/10.1016/j.jvir.2007.10.031] [PMID: 18341958]
[28]
MacColl E, Khalil RA. Matrix metalloproteinases as regulators of vein structure and function: implications in chronic venous disease. J Pharmacol Exp Ther 2015; 355(3): 410-28.
[http://dx.doi.org/10.1124/jpet.115.227330] [PMID: 26319699]
[29]
Benjamin MM, Khalil RA. Matrix metalloproteinase inhibitors as investigative tools in the pathogenesis and management of vascular disease matrix metalloproteinase inhibitors. Springer 2012; pp. 209-79.
[30]
Rothenberg ML, Nelson AR, Hande KR. New drugs on the horizon: matrix metalloproteinase inhibitors. Stem Cells 1999; 17(4): 237-40.
[http://dx.doi.org/10.1002/stem.170237] [PMID: 10437989]

Rights & Permissions Print Cite
Article Metrics
20
1
World Health Day
© 2024 Bentham Science Publishers | Privacy Policy