E-ISSN 2231-3206 | ISSN 2320-4672
 

Original Research 


Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami.

Cited by (3)

Abstract
Background: Atherosclerosis is a chronic inflammation disease that is caused by the interaction between monocyte and endothelial injury in tunica intima. One of the major factor of atherosclerosis is dyslipidemia. Chronic dyslipidemia, especially hypercholesterolemia, can directly alter endothelial cell through reactive oxygen species (ROS) production that oxidizes low-density lipoprotein (LDL) to become oxidized LDL (Ox-LDL). Proinflammatory cytokines, the products of perivascular adipocyte tissue (PVAT), may draw macrophage. Macrophage then engulfs Ox-LDL and becomes foam cell within tunica intima. Lipoprotein-associated phospholipase A2 (Lp-pLA2) is an enzyme that cleaves Ox-LDL to become proatherosclerotic products. Darapladib, an Lp-pLA2 inhibitor, is expected to inhibit atherosclerotic lesion progressivity.

Aims and Objective: To know the effects of darapladib on Ox-LDL level, PVAT thickness, and foam cell number.

Materials and Methods: This study used in vivo posttest controlled group design with two time series. Thirty male Sprague–Dawley rats divided into two group based on time series (8 weeks and 16 weeks). Each time serial was divided into three groups which were: standard diet group ;high-fat diet group; and dyslipidemia model with darapladib administration group with dose of 200 mg/200 g body weight (BW). The parameters that was measured in this study were lipid profile [total cholesterol, LDL/very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL)], Ox-LDL level, number of foam cells, and PVAT thickness.

Result: Ox-LDL level and foam cell number decreased significantly (p = 0.000 and p = 0.005, respectively), while PVAT thickness did not show significant difference (p = 0.912).

Conclusion: In this, study, it has been proven that darapladib decreases Ox-LDL levels and foam cell numbers but not in PVAT thickness, even though a decreasing pattern was observed histologically. Further study needed to know the optimum dosage of darapladib administration.

Key words: Darapladib; Lp-PLA2; Ox-LDL; Foam Cell; PVAT; Dyslipidemia


 
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REFERENCES
1. WHO. 2008. Cardiovascular Diseases. Geneva: WHO Available at: http://www.who.int/mediacentre/factsheets/fs317/en/.
2. Jaggi H, Kearns EH. Risk Factors in Coronary Artery Disease. Missouri: University of Missouri-Columbia School of Health Proffesions, 2012 Available at: http://shp.missouri.edu/vhct/case2000/conclusion.htm.
3. Lam JYT. Atherosclerosis. 2012 Available at: http://www.merckmanuals.com/professional/cardiovascular_disorders/arteriosclerosis/atherosclerosis.html.
4. Homoud MK. Coronary Artery Disease. Boston: Tufts New England Medical Center, 2008. pp. 1-13.
5. Stephens E. Peripheral Vascular Disease. 2014. Available from: http://emedicine.medscape.com/article/761556-overview#a0101.
6. Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol. 2007; 27(1):15-26. [DOI via Crossref]    [Pubmed]   
7. Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology, 8th edn. Philadelphia: Saunders, 2007.
8. Shashkin P, Dragulev B, Ley K. Macrophage differentiation to foam cells. Curr Pharm Des. 2005;11(23):3061-72. [DOI via Crossref]    [Pubmed]   
9. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoproteinassociated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol. 2006;26(7): 1586-93. [DOI via Crossref]    [Pubmed]   
10. Wang T, Palucci D, Law K, Yanagawa B, Yam J, Butany J. Atherosclerosis: pathogenesis and pathology. Diagn Histopathol. 2012;18(11):461-7. [DOI via Crossref]   
11. Mayer O, Seidlerová J, Vaněk J, Kielbergerová L, Bruthans J, Filipovský J, et al. The association between uncarboxylated matrix Gla protein and lipoprotein-associated phospholipase A2. Maturitas. 2015;80(1):82-8. [DOI via Crossref]    [Pubmed]   
12. Verhagen SN, Visseren FL. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis. 2011;214(1):3-10. [DOI via Crossref]    [Pubmed]   
13. Eringa EC, Bakker W, van Hinsbergh VW. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Vascul Pharmacol. 2012;56(5-6):204-9.
14. Karakas M, Koenig W. Lp-PLA2 inhibition—the atherosclerosis panacea? Pharmaceuticals. 2010;3(5):1360-73. [DOI via Crossref]    [PMC Free Fulltext]   
15. Boekholdt SM, de Winter RJ, Kastelein JJ. Inhibition of lipoproteinassociated phospholipase activity by darapladib: shifting gears in cardiovascular drug development: are antiinflammatory drugs the next frontier? Circulation. 2008;118(11):1120-2. [DOI via Crossref]    [Pubmed]   
16. Riley RF, Corson MA. Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease. IDrugs. 2009;12(10):648-55.
17. Masangkay EG. GSK’s Darapladib Phase III Study In ACS Misses Primary Endpoint. 2014 Available at: http://www.clinicalleader. com/doc/gsk-s-darapladib-phase-iii-study-in-acs-misses-primaryendpoint-0001.
18. Bobryshev YV. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006;37(3):208-22. [DOI via Crossref]    [Pubmed]   
19. Hong L, Xie ZZ, Du YH, Tang YB, Tao J, Lv XF, Guan YY. Alteration of volume-regulated chloride channel during macrophage-derived foam cell formation in atherosclerosis. Atherosclerosis. 2011;216(1):59-66. [DOI via Crossref]    [Pubmed]   
20. Steen DL, Donoghue MLO. Lp-PLA2 inhibitors for the reduction of cardiovascular events. Cardiol Ther. 2013;2:125-34. [DOI via Crossref]    [Pubmed]    [PMC Free Fulltext]   
21. Fiorucci S, Cipriani S, Baldelli F, Mencarelli A. Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog Lipid Res. 2010;49(2):171-85. [DOI via Crossref]    [Pubmed]   
22. O’Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, et al. Study design and rationale for the Stabilization of pLaques using Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J. 2011;162(4):613-9. [DOI via Crossref]    [Pubmed]   
23. Do KR, Kim C, Chang B, An SSA, Shin JM, Yea SJ, et al. Darapladib binds to lipoprotein-associated phospholipase A2 with meaningful interaction. Bull Korean Chem Soc. 2014;35(1):250-2. [DOI via Crossref]   
24. Macphee CH, Nelson J, Zalewski A. Role of lipoprotein-associated phospholipase A2 in atherosclerosis and is potential as a therapeutic target. Curr Opin Pharmacol. 2006;6(2):154-61. [DOI via Crossref]    [Pubmed]   
25. Wilensky RL, Shi Y, Mohler ER, Hamamdzic D, Burgert ME, Li J, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008;14(10):1059-66. [DOI via Crossref]    [Pubmed]    [PMC Free Fulltext]   
26. Gonc¸alves I, Edsfeldt A, Ko NY, Grufman H, Berg K, Bjorkbacka H, et al. Evidence supporting a key role of Lp-PLA2-generated inflammation. Arterioscler Thromb Vasc Biol. 2012;32(6):1505-12. [DOI via Crossref]    [Pubmed]   
27. Papakyriakou A, Stamatakis GM, Demopoulos CA. Computational investigation of darapladib and rilapladib binding to platelet activating factor receptor. A possible mechanism of their involvement in atherosclerosis. Int J Chem. 2014;6(1):50-60.
28. Marin-Garcia J, Goldenthal MJ, Moe GW. Aging and the Heart: Post Genomic View. , New York: Springer, 2007.
29. Tousoulis D, Papageorgiou N, Androulakis E, Stefanadis C. Lp-Pla2—a novel marker of atherosclerosis: to treat or not to treat? Int J Cardiol. 2013;165(2):213-6. [DOI via Crossref]    [Pubmed]   
30. Lerman A, Mcconnell JP. Lipoprotein-associated phospholipase A2: a risk marker or a risk factor? Am J Cardiol. 2008;101:11F-22F.
31. Douglas G, Channon KM. The pathogenesis of atherosclerosis. Medicine. 2014;42(9):480-4. [DOI via Crossref]   

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How to Cite this Article
Pubmed Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. Natl J Physiol Pharm Pharmacol. 2016; 6(1): 52-58. doi:10.5455/njppp.2015.5.2909201580


Web Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. https://www.njppp.com/?mno=203195 [Access: August 03, 2022]. doi:10.5455/njppp.2015.5.2909201580


AMA (American Medical Association) Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. Natl J Physiol Pharm Pharmacol. 2016; 6(1): 52-58. doi:10.5455/njppp.2015.5.2909201580



Vancouver/ICMJE Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. Natl J Physiol Pharm Pharmacol. (2016), [cited August 03, 2022]; 6(1): 52-58. doi:10.5455/njppp.2015.5.2909201580



Harvard Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami (2016) Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. Natl J Physiol Pharm Pharmacol, 6 (1), 52-58. doi:10.5455/njppp.2015.5.2909201580



Turabian Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. 2016. Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. National Journal of Physiology, Pharmacy and Pharmacology, 6 (1), 52-58. doi:10.5455/njppp.2015.5.2909201580



Chicago Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. "Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats." National Journal of Physiology, Pharmacy and Pharmacology 6 (2016), 52-58. doi:10.5455/njppp.2015.5.2909201580



MLA (The Modern Language Association) Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami. "Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats." National Journal of Physiology, Pharmacy and Pharmacology 6.1 (2016), 52-58. Print. doi:10.5455/njppp.2015.5.2909201580



APA (American Psychological Association) Style

Teuku Heriansyah, Titin Andri Wihastuti, Kenty Wantri Anita, Agustin Iskandar, Riski Bagus Suhendra, Patan Ahmad Setiabudi, Lintang Widya Sishartami (2016) Atherogenesis inhibition by darapladib administration in dyslipidemia model Sprague–Dawley rats. National Journal of Physiology, Pharmacy and Pharmacology, 6 (1), 52-58. doi:10.5455/njppp.2015.5.2909201580