Skip to main content
SpringerLink
Log in

Anti-atherosclerotic effects of pravastatin in brachiocephalic artery in comparison with en face aorta and aortic roots in ApoE/LDLR−/− mice

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Cholesterol-dependent and independent mechanisms were proposed to explain anti-atherosclerotic action of statins in humans. However, their effects in murine models of atherosclerosis have not been consistently demonstrated. Here, we studied the effects of pravastatin on atherosclerosis in ApoE/LDLR−/− mice fed a control and atherogenic diet.

Methods

ApoE/LDLR−/− mice were fed a control (CHOW) or an atherogenic (Low Carbohydrate High Protein, LCHP) diet. Two doses of pravastatin (40 mg/kg and 100 mg/kg) were used. The anti-atherosclerotic effects of pravastatin in en face aorta, cross-sections of aortic roots and brachiocephalic artery (BCA) were analysed. The lipid profile was determined. Fourier Transform Infrared Spectroscopy followed by Fuzzy C-Means (FCM) clustering was used for the quantitative assessment of plaque composition.

Results

Treatment with pravastatin (100 mg/kg) decreased total and LDL cholesterol only in the LCHP group, but displayed a pronounced anti-atherosclerotic effect in BCA and abdominal aorta. The anti-atherosclerotic effect of pravastatin (100 mg/kg) in BCA was associated with significant alterations of the chemical plaque composition, including a fall in cholesterol and cholesterol esters contents independently on total cholesterol and LDL concentration in plasma.

Conclusions

Pravastatin at high (100 mg/kg), but not low dose displayed a pronounced anti-atherosclerotic effect in ApoE/LDLR−/− mice fed a CHOW or LCHP diet that was remarkable in BCA, visible in en face aorta, whereas it was not observed in aortic roots, suggesting that previous inconsistencies might have been due to the various sites of atherosclerotic plaque analysis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Whitman SC. A practical approach to using mice in atherosclerosis research. Clin Biochem Rev 2004;25(1):81–93.

    PubMed  PubMed Central  Google Scholar 

  2. Takagi T, Matsuda M, Abe M, Kobayashi H, Fukuhara A, Komuro R, et al. Effect of pravastatin on the development of diabetes and adiponectin production. Atherosclerosis 2008;196(1):114–21.

    Article  CAS  Google Scholar 

  3. Zadelaar S, Kleemann R, Verschuren L, de Vries-Van der Weij J, van der Hoorn J, Princen HM, et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 2007;27(8):1706–21.

    Article  CAS  Google Scholar 

  4. Shaposhnik Z, Wang X, Trias J, Fraser H, Lusis AJ. The synergistic inhibition of atherogenesis in apoE2/2 mice between pravastatin and the sPLA2 inhibitor varespladib (A-002). J Lipid Res 2009;50:623–9.

    Article  CAS  Google Scholar 

  5. Bea F, Blessing E, Bennett B, Levitz M, Wallace EP, Rosenfeld ME. Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering. Arterioscler Thromb Vasc Biol 2002;22(11):1832–7.

    Article  CAS  Google Scholar 

  6. Marzoll A, Melchior-Becker A, Cipollone F, Fischer JW. Small leucine-rich proteoglycans in atherosclerotic lesions: novel targets of chronic statin treatment? Cell Mol Med 2011;15(2):232–43.

    Article  CAS  Google Scholar 

  7. van der Hoorn JWA, Kleemann R, Havekes LM, Kooistr T, Princen HMG, Jukem JW. Olmesartan and pravastatin additively reduce development of atherosclerosis in APOEM3Leiden transgenic mice. J Hypertens 2007;25:2454–62.

    Article  Google Scholar 

  8. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, et al. Reduction of stroke events with pravastatin: the prospective pravastatin pooling (PPP) project. Circulation 2001;103:387–92.

    Article  CAS  Google Scholar 

  9. Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol 2009;54(25):2358–62.

    Article  CAS  Google Scholar 

  10. 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;55:2103–12.

    Article  Google Scholar 

  11. Foo SY, Heller ER, Wykrzykowska J, Sullivan ChJ, Manning-Tobin JJ, Moore KJ, et al. Vascular effects of a low-carbohydrate high-protein diet. Proc Natl Acad Sci U S A 2009;106(36):15418–23.

    Article  CAS  Google Scholar 

  12. Kostogrys RB, Franczyk-Żarów M, Maślak E, Gajda M, Mateuszuk Ł, Jackson CL, et al. Low carbohydrate, high protein diet promotes atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice (apoE/LDLR−/−). Atherosclerosis 2012;223:327–33.

    Article  CAS  Google Scholar 

  13. Wang J, Geng Y-J, Guo B, Klima T, Lal BN, Willerson JT, et al. Near-infrared spectroscopic characterization of human advanced atherosclerotic plaques. J Am Coll Cardiol 2002;39(8):1305–13.

    Article  Google Scholar 

  14. Caplan JD, Waxman S, Nesto RW, Muller JE. Near-infrared spectrscopy for the detection of vulnerable coronary artery plaques. J Am Coll Cardiol 2006;47(8): C92–6.

    Article  Google Scholar 

  15. Gardner CM, Tan H, Hull EL, Lisauskas JB, Sum ST, Meese TM, et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging 2008;1(5): 638–48.

    Article  Google Scholar 

  16. Wrobel TP, Majzner K, Baranska M. Protein profile in vascular wall of atherosclerotic mice analyzed ex vivo using FT-IR spectroscopy. Spectrochim Acta A Mol Biomol Spectrosc 2012;96:940–5.

    Article  CAS  Google Scholar 

  17. Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS. The two-receptor model of lipoprotein clearance: tests of the hypothesis in knockout mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci U S A 1994;91:4431–5.

    Article  CAS  Google Scholar 

  18. Reeves PG, Nielsen FH, Fahey GC. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc Writing Committee on the reformulation of the AIN-76A rodent diet. J Nutr 1993;123:1939–51.

    Article  CAS  Google Scholar 

  19. Lloyd DJ, Helmering J, Kaufman SA, Turk J, Silva M, Vasquez S, et al. A volumetric method for quantifying atherosclerosis in mice by using microCT: comparison to en face. PLoS One 2011;6(April (4)):18800, doi:https://doi.org/10.1371/journal.pone.0018800.

    Article  Google Scholar 

  20. Rosenfeld ME, Carson KG, Johnson JL, Williams H, Jackson CL, Schwartz SM. Animal models of spontaneous plaque rupture: the holy grail of experimental atherosclerosis research. Curr Atheroscler Rep 2002;4(3):238–42.

    Article  Google Scholar 

  21. Reardon CA, Blachowicz L, Lukens J, Nissenbaum M, Getz GS. Genetic background selectively influences innominate artery atherosclerosis: immune system deficiency as a probe. Arterioscler Thromb Vasc Biol 2003;23(8): 1449–54.

    Article  CAS  Google Scholar 

  22. Schroeter MR, Humboldt T, Schäfer K, Konstantinides S. Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice. Atherosclerosis 2009;205: 63–73.

    Article  CAS  Google Scholar 

  23. Nachtigal P, Pospisilova N, Jamborova G, Pospechova K, Solichova D, Andrys C, et al. Atorvastatin has hypolipidemic and anti-inflammatory effects in apoE/ LDL receptor-double-knockout mice. Life Sci 2008;82(13–14):708–17.

    Article  CAS  Google Scholar 

  24. Kuhnast S, Louwe MC, Heemskerk MM, Pieterman EJ, van Klinken JB, van den Berg SAA, et al. Niacin reduces atherosclerosis development in APOE*3Leiden. CETP mice mainly by reducing NonHDL cholesterol. PLoS One 2013;8(June (6)):e66467, doi:https://doi.org/10.1371/journal.pone.0066467.

    Article  Google Scholar 

  25. Kwak BR, Veillard N, Pelli G, Mulhaupt F, James RW, Chanson M, et al. Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation 2003;107(7):1033–9.

    Article  CAS  Google Scholar 

  26. Dunoyer-Geindre S, Kwak BR, Pelli G, Roth I, Satta N, Fish RJ, et al. Immunization of LDL receptor-deficient mice with beta2-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques. Thromb Haemost 2007;97(1):129–38.

    Article  CAS  Google Scholar 

  27. Zhou X, Li D, Yan W, Li W. Pravastatin prevents aortic atherosclerosis via modulation of signal transduction and activation of transcription 3 (STAT3) to attenuate interleukin-6 (IL-6) action in ApoE knockout mice. Int J Mol Sci 2008;9(11):2253–64.

    Article  CAS  Google Scholar 

  28. Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins. Circ Res 2007;100(10):1394–405.

    Article  CAS  Google Scholar 

  29. Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator- activated receptors and cancers: complex stories. Nat Rev Cancer 2004;4(1):61–70.

    Article  CAS  Google Scholar 

  30. Prinz V, Endres M. Statins and stroke: prevention and beyond. Curr Opin Neurol 2011;24(1):75–80.

    Article  CAS  Google Scholar 

  31. Bruder-Nascimento T, Callera GE, Montezano AC, He Y, Antunes TT, Cat AN, et al. Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive nox-dependent pathways. Clin Sci (Lond) 2015;128(7):411–23.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15 A, Kraków, 31-501, Poland

    Renata B. Kostogrys

  2. Department of Human Nutrition, Faculty of Food Technology, Agricultural University of Kraków, Balicka 122, Kraków, 30-149, Poland

    Magdalena Franczyk-Zarow, Izabela Czyzynska-Cichon, Anna Drahun & Angelika Manterys

  3. Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, Kraków, Poland

    Marlena Gasior-Glogowska, Edyta Kus, Agnieszka Jasztal, Tomasz P. Wrobel, Malgorzata Baranska, Izabela Czyzynska-Cichon & Stefan Chlopicki

  4. Faculty of Chemistry, Jagiellonian University, 3 Ingardena Str., Kraków, 30-060, Poland

    Malgorzata Baranska

  5. Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, Kraków, 31-531, Poland

    Stefan Chlopicki

Authors
  1. Renata B. Kostogrys
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdalena Franczyk-Zarow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marlena Gasior-Glogowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edyta Kus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Agnieszka Jasztal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomasz P. Wrobel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Malgorzata Baranska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Izabela Czyzynska-Cichon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Drahun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angelika Manterys
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefan Chlopicki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renata B. Kostogrys.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kostogrys, R.B., Franczyk-Zarow, M., Gasior-Glogowska, M. et al. Anti-atherosclerotic effects of pravastatin in brachiocephalic artery in comparison with en face aorta and aortic roots in ApoE/LDLR−/− mice. Pharmacol. Rep 69, 112–118 (2017). https://doi.org/10.1016/j.pharep.2016.09.014

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2016.09.014

Keywords

Search

Navigation