Skip to main content
Log in

Haemostatic risk factors in dyslipidemic rabbits: role of 10-dehydrogingerdione as a new hypolipemic agent

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Micro and macrovascular complications occurring during hyperlipidemia are mostly attributed to haemostatic impairment and vascular endothelial dysfunction. Cholesteryl ester transfer protein (CETP) inhibitors have been emerged recently as promising hypocholesterolemic agents to confer protection against lipid-mediated atherosclerosis. Therefore, 10-dehydrogingerdione (DHGD), a novel CETP inhibitor isolated from ginger rhizomes, was selected as a natural product in the present study to illustrate its effect on haemostatic impairment associated with hyperlipidemia as compared to a currently used hypocholesterolemic agent, atorvastatin (ATOR). Rabbits were fed a high cholesterol diet (HCD) and divided into three groups. One group served as control group while the other groups received DHGD or ATOR. Dyslipidemic rabbits showed a significant increase in serum endothelin-1, ischemia modified albumin, plasminogen activator inhibitor-1, prothrombin fragments (1+2) and plasma fibrinogen along with a decrease of nitric oxide level in serum. Daily administration of ATOR or DHGD significantly decreased the aforementioned coagulation and ischemia biomarkers and increased serum nitric oxide. DHGD (natural) results seem to be more remarkable as compared to ATOR (synthetic).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ABSU:

Absorbance units

ADMA:

Asymmetric dimethyl arginine

ANOVA:

Analysis of variance

ATOR:

Atorvastatin

CETP:

Cholesteryl ester transfer protein

CRP:

C-reactive protein

DHGD:

10-Dehydrogingerdione

ELISA:

Enzyme-linked immunosorbent assay

eNOS:

Endothelial nitric oxide synthase

ET-1:

Endothelin-1

FIB:

Fibrinogen

HCD:

High cholesterol diet

HDL-C:

High density lipoprotein cholesterol

IMA:

Ischemia modified albumin

LDL-C:

Low density lipoprotein cholesterol

NC:

Normal control

NO:

Nitric oxide

ox-LDL:

Oxidized low density lipoprotein

PAI-1:

Plasminogen activator inhibitor-1

PF1+2:

Prothrombin fragment (1+2)

ROS:

Reactive oxygen species

References

  1. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Sobel BE, Taatjes DJ, Schneider DJ (2003) Intramural plasminogen activator inhibitor type-1 and coronary atherosclerosis. Artherioscler Thromb Vasc Biol 23:1979–1989

    Article  CAS  Google Scholar 

  3. Smith A, Patterson C, Yarnell J et al (2005) Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly study. Circulation 112:3080–3087

    Article  PubMed  Google Scholar 

  4. Berberoğlu M, Evliyaoğlu O, Adiyaman P et al (2006) Plasminogen activator inhibitor-1 (PAI-1) gene polymorphism (-675 4G/5G) associated with obesity and vascular risk in children. J Pediatr Endocrinol Metab 19:741–748

    PubMed  Google Scholar 

  5. Kuniyasu A, Tokunaga M, Yamamoto T et al (2011) Oxidized LDL and lyso-phosphatidyl choline stimulate plasminogen activator inhibitor-1 expres-sion through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes. Biochim Biophys Acta 1811:153–162

    Article  CAS  PubMed  Google Scholar 

  6. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695

    Article  CAS  PubMed  Google Scholar 

  7. Eriksson EE (2004) Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol 15:553–558

    Article  CAS  PubMed  Google Scholar 

  8. Bhandary B, Lee GH, Marahatta A et al (2012) Water extracts of immature Rubus coreanus regulate lipid metabolism in liver cells. Biol Pharm Bull 35:1907–1913

    Article  CAS  PubMed  Google Scholar 

  9. Akalin A, Temiz G, Akcar N, Sensoy B (2008) Short term effects of atorvastatin on endothelial functions and oxidized LDL levels in patients with type 2 diabetes. Endocr J 55:861–866

    Article  CAS  PubMed  Google Scholar 

  10. Ishihara Y, Ohmori K, Mizukawa M et al (2010) Beneficial direct adipotropic actions of pitavastatin in vitro and their manifestations in obese mice. Atherosclerosis 212:131–138

    Article  CAS  PubMed  Google Scholar 

  11. Lee SH, Cho KI, Kim JY et al (2012) Non-lipideffects of rosuvastatin-fenofibrate combination therapy in high-risk Asian patients with mixed hyperlipidemia. Atherosclerosis 221:169–175

    Article  CAS  PubMed  Google Scholar 

  12. Forrester JS, Makkar R, Shah PK (2005) Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians. Circulation 111:1847–1854

    Article  CAS  PubMed  Google Scholar 

  13. Mohammadpour AH, Akhlaghi F (2013) Future of cholesteryl ester transfer protein (CETP) inhibitors: a pharmacological perspective. Clin Pharmacokinet 52(8):615–626

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Jin S, Cho KH (2011) Water extracts of cinnamon and clove exhibits potent inhibition of protein glycation and anti-atherosclerotic activity in vitro and in vivo hypolipidemic activity in zebrafish. Food Chem Toxicol 49:1521–1529

    Article  CAS  PubMed  Google Scholar 

  15. Ghorai M, Mandal SC, Pal M et al (2000) A comparative study on hypocholesterolaemic effect of allicin, whole germinated seeds of bengal gram and guggulipid of gum gugglu. Phytother Res 14:200–202

    Article  CAS  PubMed  Google Scholar 

  16. Choi SY, Park GS, Lee SY et al (2011) The conformation and CETP inhibitory activity of [10]-dehydrogingerdione isolated from Zingiber officinale. Arch Pharm Res 34:727–731

    Article  CAS  PubMed  Google Scholar 

  17. El-Seweidy MM, Abdallah FR, Eldohmy S et al (2013) 10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidaemic rabbits. Atherosclerosis 213:334–340

    Article  Google Scholar 

  18. Chapman MJ (1980) Animal lipoproteins: chemistry, structure, and comparative aspects. J Lipid Res 21:789–853

    CAS  PubMed  Google Scholar 

  19. Fan J, Challah M, Watanabe T (1999) Transgenic rabbit models for biomedical research: current status, basic methods and future perspectives. Pathol Int 49:583–594

    Article  CAS  PubMed  Google Scholar 

  20. Madhumathi BG, Venkataranganna MV, Gopumadhavan S et al (2006) Induction and evaluation of atherosclerosis in New Zealand white rabbits. Indian J Exp Biol 44:203–208

    CAS  PubMed  Google Scholar 

  21. Kitahara M, Kanaki T, Ishii I, Saito Y (2010) Atherosclerosis induced by chronic inhibition of the synthesis of nitric oxide in moderately hypercholesterolaemic rabbits is suppressed by pitavastatin. Br J Pharmacol 159:1418–1428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Siempos II, Maniatis NA, Kopterides P et al (2010) Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model. Crit Care Med 38:1321–1328

    CAS  PubMed  Google Scholar 

  23. Bar-Or D, Lau E, Winkler JV (2000) A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia: a preliminary report. J Emerg Med 19:311–315

    Article  CAS  PubMed  Google Scholar 

  24. Moshage H, Kok B, Heuzenga JR, Jansen PL (1995) Nitrite and nitrate determination in plasma: a critical evaluation. Clin Chem 41:892–896

    CAS  PubMed  Google Scholar 

  25. Clauss A (1957) Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol 17:237–246

    Article  CAS  PubMed  Google Scholar 

  26. Wei J, Ma C, Wang X (2006) Simvastatin inhibits tissue factor and plasminogen activator inhibitor-1 expression of glomerular mesangial cells in hypercholesterolemic rabbits. Biomed Res 27:149–155

    Article  PubMed  Google Scholar 

  27. Stoll LL, McCormick ML, Denning GM, Weintraub NL (2004) Antioxidant effects of statins. Drug Today 40:975–990

    Article  CAS  Google Scholar 

  28. Hogue JC, Lamarche B, Tremblay AJ et al (2008) Differntial effect of ator-vastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus. Metabolism 57:380–386

    Article  CAS  PubMed  Google Scholar 

  29. Song CY, Kim BC, Lee HS (2008) Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-β1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. Transl Res 151:27–35

    Article  CAS  PubMed  Google Scholar 

  30. Nomura S, Taniura T, Shouzu A et al (2012) Effects of pitavastatin on plasminogen activator inhibitor-1 in hyperlipidemic patients. Int J Gen Med 5:535–540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Deguchi H, Fernández JA, Griffin JH (2007) Plasma cholesteryl ester transfer protein and blood coagulability. Thromb Haemost 98:1160–1164

    CAS  PubMed  Google Scholar 

  32. Deguchi H, Pecheniuk NM, Elias DJ et al (2005) High-density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation 112(6):893–899

    Article  CAS  PubMed  Google Scholar 

  33. Verma SK, Singh M, Jain P, Bordia A (2004) Protective effect of ginger, Zingiber officinale Rosc on experimental atherosclerosis in rabbits. Indian J Exp Biol 42:736–738

    CAS  PubMed  Google Scholar 

  34. Böger RH, Lentz SR, Bode-Böger SM et al (2001) Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocysteinaemia in humans. Clin Sci (Lond) 100:161–167

    Article  Google Scholar 

  35. Szilvássy Z, Csont T, Páli T et al (2001) Nitric oxide, peroxynitrite and cGMP in atherosclerosis-induced hypertension in rabbits: beneficial effects of cicletanine. J Vasc Res 38:39–46

    Article  PubMed  Google Scholar 

  36. Bolayirli IM, Aslan M, Balci H et al (2007) Effects of atorvastatin therapy on hypercholesterolemic rabbits with respect to oxidative stress, nitric oxide pathway and homocysteine. Life Sci 81:121–127

    Article  CAS  PubMed  Google Scholar 

  37. Maeso R, Aragoncillo P, Navarro-Cid J et al (2000) Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits. Gen Pharmacol 34:263–272

    Article  CAS  PubMed  Google Scholar 

  38. Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J et al (1998) Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 101:2711–2719

    Article  PubMed Central  PubMed  Google Scholar 

  39. Rasmusen C, Cynober L, Couderc R (2005) Arginine and statins: relationship between the nitric oxide pathway and the atherosclerosis development. Ann Biol Clin (Paris). 63:443–455

    CAS  PubMed  Google Scholar 

  40. Rajamannan NM, Subramaniam M, Stock SR et al (2005) Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart 91:806–810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Vassalle C, Pratali L, Boni C et al (2008) An oxidative stress score as a combined measure of the pro-oxidant and anti-oxidant counterparts in patients with coronary artery disease. Clin Biochem 41:1162–1167

    Article  CAS  PubMed  Google Scholar 

  42. Roy D, Quiles J, Gaze DC et al (2006) Role of reactive oxygen species on the formation of the novel diagnostic marker ischemia modified albumin. Heart 92:113–114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Sbarouni E, Georgiadou P, Voudris V (2011) Ischemia modified albumin changes: review and clinical implications. Clin Chem Lab Med 49:177–184

    Article  CAS  PubMed  Google Scholar 

  44. Duarte MM, Rocha JB, Moresco RN et al (2009) Association between ischemia-modified albumin, lipids and inflammation biomarkers in patients with hypercholesterolemia. Clin Biochem 42:666–671

    Article  CAS  PubMed  Google Scholar 

  45. Bogavac-Stanojević N, Jelić-Ivanović Z, Spasojević-Kalimanovska V et al (2007) Lipid and inflammatory markers for the prediction of coronary artery disease: a multi-marker approach. Clin Biochem 40:1000–1006

    Article  PubMed  Google Scholar 

  46. Abramson JL, Hooper WC, Jones DP et al (2005) Association between novel oxidative stress markers and C-reactive protein among adults without clinical coronary heart disease. Atherosclerosis 178:115–121

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors had no conflict of interest to disclose and declare that they did not receive any financial support for this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hebatallah Husseini Atteia.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-Seweidy, M.M., Asker, M.ES., Eldahmy, S.I. et al. Haemostatic risk factors in dyslipidemic rabbits: role of 10-dehydrogingerdione as a new hypolipemic agent. J Thromb Thrombolysis 39, 196–202 (2015). https://doi.org/10.1007/s11239-014-1150-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-014-1150-x

Keywords

Navigation