DARAPLADIB INHIBIT ADHESION MOLECULE EXPRESSION IN AORTA AT EARLY STAGES OF ATHEROSCLEROSIS USING SPRAGUE-DAWLEY TYPE 2 DIABETES MELLITUS MODEL

  • Heriansyah T Department of Cardiology, Syiah Kuala University, Aceh, Sumatera, Indonesia http://orcid.org/0000-0002-1419-7225
  • Hanifa H Department of Biomedical, Brawijaya University, Malang, East Java, Indonesia.
  • Andarini S Department of Biomedical, Brawijaya University, Malang, East Java, Indonesia.
  • Wihastuti Titin Andri Department of Biomedical, Brawijaya University, Malang, East Java, Indonesia.

Abstract

Objective: Hyperglycemia and hyperlipidemia in diabetes mellitus (DM) can lead an atherosclerosis. The increase of low-density lipoprotein level in DM and atherosclerosis is correlated with lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids. LysoPC regulated inflammation mediators, include cytokines, adhesion molecules (such as vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecules-1 [ICAM-1]), and monocyte chemoattractant protein-1 (MCP-1) chemotactic. Darapladib is known as a Lp-PLA2 specific inhibitor. It is also considered to be an atherosclerosis treatment. The aim of this study is to know darapladib effect on VCAM-1 and ICAM-1 aorta expression in early stages of atherosclerosis using Sprague-Dawley Type 2 DM (T2DM) model.

Methods: About 30 Spraque-Dawley rats are divided into three main groups: Normal, T2DM, and T2DM with darapladib administration group. Each group consists of 2 serials treatment time: 8 and 16 weeks treatment group. Fasting blood glucose, resistance insulin, and lipid profile were measured and analyzed to ensure T2DM model. VCAM-1 and ICAM-1 expression were measured using double staining immunofluorescence. Each data were analyzed using one-way ANOVA.

Results: There is a significant difference in VCAM-1 expression in T2DM group (8 and 16 weeks), with p=0.011 and 0.034 (p<0.05), respectively. Mean while, a significant difference for ICAM-1 only showed in 8 weeks T2DM group with p=0.03 (p<0.05). Moreover, there is a decreasing trend in 16 weeks T2DM group.

Conclusion: Our results showed that darapladib can decrease VCAM-1 and ICAM-1 aorta expression in early stages of atherosclerosis using Sprague- Dawley T2DM model. This showed another evidence of darapladib as atherosclerosis treatment.

Keywords: Darapladib, Vascular cell adhesion molecule-1, Intercellular adhesion molecules-1, Atherosclerosis, Type 2 diabetes mellitus.

References

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011;34(1):S62. IDF Atlas. IDF Diabetes Atlas. 6th ed. Brussels: IDF; 2013. p. 9.
3. Chait A, Bornfeldt KE. Diabetes and atherosclerosis: Is there a role for hyperglycemia? J Lipid Res 2009;50 Suppl: S335-9.
4. Heriansyah T, Wihastuti TA, Anita KW, Iskandar A, Suhendra RB, Setiabudi PA, et al. Atherogenesis inhibition by darapladib administration in dyslipidemia model sprague-dawley rats. Natl J Physiol Pharm Pharmacol 2015;2:2.
5. Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: Molecular mechanisms. Cardiovasc Diabetol 2002;1:1.
6. Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007;27(11):2292-301.
7. Wihastuti TA, Sargowo D, Tjokroprawiro A, Permatasari N, Widodo MA, Soeharto S. Vasa vasorum anti-angiogenesis through H2O2, HIF-1a, NF-?B, and iNOS inhibition by mangosteen pericarp ethanolic extract (Garcinia mangostana Linn) in hypercholesterol-diet-given Rattus norvegicus wistar strain. Vasc Health Risk Manag 2014;10:523-31.
8. Wihastuti TA, Heriansyah T, Soraya M, Wijayanti M, Firani N, Iskandar A, et al. Inhibition of oxidative stress in hypercolerterolemic rats by soy milk. J Cardiovasc Disease Res 2016;7(2):74-82.
9. Belma H, Dhalla N. Diabetic Cardiomyopathy: Biochemical and Molecular Mechanism. New York: Springer-Verlag; 2014. p. 221.
10. Carlquist JF, Muhlestein JB, Anderson JL. Lipoprotein-associated phospholipase A2: A new biomarker for cardiovascular risk assessment and potential therapeutic target. Expert Rev Mol Diagn 2007;7:511-7.
11. Thompson PL, Nidorf SM, Eikelboom J. Targeting the unstable plaque in acute coronary syndromes. Clin Ther 2013;35(8):1099-10.
12. Heriansyah T, Adam AA, Wihastuti TA, Rohman MS. Elaborate evaluation of serum and tissue oxidized LDL level with darapladib therapy: A feasible diagnostic marker for early atherogenesis. Asian Pac J Trop Biomed 2016. DOI: 10.1016/j.apjtb.2016.11.014.
13. Burns TA, Geor RJ, Mudge MC, McCutcheon LJ, Hinchcliff KW, Belknap JK. Proinflammatory cytokine and chemokine gene expression profiles in subcutaneous and visceral adipose tissue depots of insulin-resistant and insulin-sensitive light breed horses. J Vet Intern Med 2010;24(4):932-9.
14. van Dijk JW, Venema M, van Mechelen W, Stehouwer CD, Hartgens F, van Loon LJ. Effect of moderate-intensity exercise versus activities of daily living on 24-hour blood glucose homeostasis in male patients with Type 2 diabetes. Diabetes Care 2013;36(11):3448-53.
15. Cacho J, Sevillano J, de Castro J, Herrera E, Ramos MP. Validation of simple indexes to assess insulin sensitivity during pregnancy in wistar and Sprague-Dawley rats. Am J Physiol Endocrinol Metab 2008;295(5):E1269-76.
16. Wilensky RL, Shi Y, Mohler ER 3rd, Hamamdzic D, Burgert ME, Li J, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008;14:1059-66.
17. Wang WY, Zhang J, Wu WY, Li J, Ma YL, Chen WH, et al. Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice. PLoS One 2011;6(8):e23425.
18. Sethi G, Sung B, Aggarwal BB. TNF: A master switch for inflammation to cancer. Front Biosci 2008;13:5094-107.
19. Frank PG, Lisanti MP. ICAM-1: Role in inflammation and in the regulation of vascular permeability. Am J Physiol Heart Circ Physiol 2008;295(3):H926-7.
20. Subhapriya S, Tomi L, Padmanaban VC. Atherosclerosis: Critical role of oxidation and inflammation. Int J Pharm Pharm Sci 2013:5(4):6-8.
21. Sumagin R, Lomakina E, Sarelius IH. Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling. Am J Physiol Heart Circ Physiol 2008;295(3):H969-77.
22. Navale AM, Paranjape AN. Role of inflammation in development of diabetic complications and commonly used inflammatory markers with respect to diabetic complications. Int J Pharm Pharm Sci 2013;5(2):1-5.
23. Hu MM, Zhang J, Wang WY, Wu WY, Ma YL, Chen WH, et al. The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosisin LDLR-deficient mice. Acta Pharmacol Sin 2011;32:1253-8.
Statistics
243 Views | 369 Downloads
How to Cite
T, H., H. H, A. S, and W. T. Andri. “DARAPLADIB INHIBIT ADHESION MOLECULE EXPRESSION IN AORTA AT EARLY STAGES OF ATHEROSCLEROSIS USING SPRAGUE-DAWLEY TYPE 2 DIABETES MELLITUS MODEL”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 10, no. 6, June 2017, pp. 373-6, doi:10.22159/ajpcr.2017.v10i6.17631.
Section
Original Article(s)