Skip to main content
Log in

Predisposition to atherosclerosis and aortic aneurysms in mice deficient in kinin B1 receptor and apolipoprotein E

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Kinin B1 receptor is involved in chronic inflammation and expressed in human atherosclerotic lesions. However, its significance for lesion development is unknown. Therefore, we investigated the effect of kinin B1 receptor deletion on the development of atherosclerosis and aortic aneurysms in apolipoprotein E-deficient (ApoE−/−) mice. Mice deficient both in ApoE and in kinin B1 receptor (ApoE−/−-B −/−1 ) were generated and analyzed for their susceptibility to atherosclerosis and aneurysm development under cholesterol rich-diet (western diet) and angiotensin II infusion. Kinin B1 receptor messenger RNA (mRNA) expression was significantly increased in ApoE−/− mice after Western-type diet. Although no difference in serum cholesterol was found between ApoE−/−-B −/−1 and ApoE−/− mice under Western-type diet, aortic lesion incidence was significantly higher in ApoE−/−-B −/−1 after this treatment. In accordance, we observed increased endothelial dysfunction in these mice. The mRNA expression of cyclic guanosine monophosphate-dependent protein kinase I, CD-11, F4/80, macrophage colony-stimulating factor, and tumor necrosis factor-alpha were increased in the aorta of double-deficient mice following Western-type diet, whereas the levels of peroxisome proliferator-activated receptor gamma protein and the activity of matrix metalloproteinase-9 activity were decreased. In addition to the increased atherosclerotic lesions, the lack of kinin B1 receptor also increased the incidence of abdominal aortic aneurysms after angiotensin II infusion. In conclusion, our results show that kinin B1 receptor deficiency aggravates atherosclerosis and aortic aneurysms under cholesterolemic conditions, supporting an antiatherogenic role for the kinin B1 receptor.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Braunwald E (1997) Shattuck lecture—cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 337:1360–1369

    Article  CAS  PubMed  Google Scholar 

  2. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  3. Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516

    Article  CAS  PubMed  Google Scholar 

  4. Golledge J, Muller J, Daugherty A, Norman P (2006) Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol 26:2605–2613

    Article  CAS  PubMed  Google Scholar 

  5. Breslow JL (1996) Mouse models of atherosclerosis. Science 272:685–688

    Article  CAS  PubMed  Google Scholar 

  6. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R (1994) ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140

    CAS  PubMed  Google Scholar 

  7. Daugherty A, Cassis LA (2004) Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 24:429–434

    Article  CAS  PubMed  Google Scholar 

  8. Regoli DC, Marceau F, Lavigne J (1981) Induction of beta 1-receptors for kinins in the rabbit by a bacterial lipopolysaccharide. Eur J Pharmacol 71:105–115

    Article  CAS  PubMed  Google Scholar 

  9. Marceau F, Hess JF, Bachvarov DR (1998) The B1 receptors for kinins. Pharmacol Rev 50:357–386

    CAS  PubMed  Google Scholar 

  10. Schanstra JP, Bataillé E, Marin Castaño ME, Barascud Y, Hirtz C, Pesquero JB, Pecher C, Gauthier F, Girolami JP, Bascands JL (1998) The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts. J Clin Invest 101:2080–2091

    Article  CAS  PubMed  Google Scholar 

  11. Rupniak NM, Boyce S, Webb JK, Williams AR, Carlson EJ, Hill RG, Borkowski JA, Hess JF (1997) Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8] bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice. Pain 71:89–97

    Article  CAS  PubMed  Google Scholar 

  12. Ahluwalia A, Perretti M (1996) Involvement of bradykinin B1 receptors in the polymorphonuclear leucocyte accumulation induced by IL-1β in vivo in the mouse. J Immunol 156:269–274

    CAS  PubMed  Google Scholar 

  13. Pesquero JB, Araujo RC, Heppenstall PA, Stuck CL, Silva JA Jr, Walther T, Oliveira SM, Pesquero J, Paiva ACM, Calixto JB, Lewin GR, Bader M (2000) Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc Natl Acad Sci U S A 97:8140–8145

    Article  CAS  PubMed  Google Scholar 

  14. McLean PG, Perretti M, Ahluwalia A (1999) Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des-Arg9bradykinin-induced coronary vasodilation. Br J Pharmacol 128:275–282

    Article  CAS  PubMed  Google Scholar 

  15. Tschope C, Spillmann F, Altmann C, Koch M, Westermann D, Dhayat N, Dhayat S, Bascands JL, Gera L, Hoffmann S, Schultheiss HP, Walther T (2004) The bradykinin B1 receptor contributes to the cardioprotective effects of AT1 blockade after experimental myocardial infarction. Cardiovasc Res 61:559–569

    Article  CAS  PubMed  Google Scholar 

  16. McLean PG, Perretti M, Ahluwalia A (2000) Kinin B(1) receptors and the cardiovascular system: regulation of expression and function. Cardiovasc Res 48:194–210

    Article  CAS  PubMed  Google Scholar 

  17. Merino VF, Todiras M, Campos LA, Saul V, Popova E, Baltatu OC, Pesquero JB, Bader M (2008) Increased susceptibility to endotoxic shock in transgenic rats with endothelial overexpression of kinin B1 receptors. J Mol Med 86:791–798

    Article  CAS  PubMed  Google Scholar 

  18. Abe KC, Mori MA, Pesquero JB (2007) Leptin deficiency leads to the regulation of kinin receptors expression in mice. Regul Pept 138:56–58

    Article  CAS  PubMed  Google Scholar 

  19. Raidoo DM, Ramsaroop R, Naidoo S, Muller-Esterl W, Bhoola KD (1997) Kinin receptors in human vascular tissue: their role in atheromatous disease. Immunopharmacology 36:153–160

    Article  CAS  PubMed  Google Scholar 

  20. Muller PY, Janovjak H, Miserez AR, Dobbie Z (2002) Processing of gene expression data generated by quantitative real-time RT–PCR. Biotechniques 32:1372–1379

    CAS  PubMed  Google Scholar 

  21. Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL (1994) ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb 14:605–616

    CAS  PubMed  Google Scholar 

  22. Xu P, Goncalves ACC, Todiras M, Rabelo LA, Sampaio WO, Moura MM, Santos SS, Luft FC, Bader M, Gross V, Alenina N, Santos RA (2008) Endothelial dysfunction and elevated blood pressure in Mas gene-deleted mice. Hypertension 51:574–580

    Article  CAS  PubMed  Google Scholar 

  23. Leber TM, Balkwill FR (1997) Zymography: a single-step staining method for quantitation of proteolytic activity on substrate gels. Anal Biochem 249:24–28

    Article  CAS  PubMed  Google Scholar 

  24. Daugherty A, Manning MW, Cassis LA (2000) Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 105:1605–1612

    Article  CAS  PubMed  Google Scholar 

  25. Daugherty A, Manning MW, Cassis LA (2001) Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J Pharmacol 134:865–870

    Article  CAS  PubMed  Google Scholar 

  26. Agata J, Miao RQ, Yayama K, Chao L, Chao J (2000) Bradykinin B(1) receptor mediates inhibition of neointima formation in rat artery after balloon angioplasty. Hypertension 36:364–370

    CAS  PubMed  Google Scholar 

  27. Lloyd-Jones DM, Bloch KD (1996) The vascular biology of nitric oxide and its role in atherogenesis. Annu Rev Med 47:365–375

    Article  CAS  PubMed  Google Scholar 

  28. Knowles JW, Reddick RL, Jennette JC, Shesely EG, Smithies O, Maeda N (2000) Enhanced atherosclerosis and kidney dysfunction in eNOS(−/−)Apoe(−/−) mice are ameliorated by enalapril treatment. J Clin Invest 105:451–458

    Article  CAS  PubMed  Google Scholar 

  29. Kuhlencordt PJ, Gyurko R, Han F, Scherrer-Crosbie M, Aretz TH, Hajjar R, Picard MH, Huang PL (2001) Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 104:448–454

    Article  CAS  PubMed  Google Scholar 

  30. Shi W, Wang X, Shih DM, Laubach VE, Navab M, Lusis AJ (2002) Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase. Circulation 105:2078–2082

    Article  CAS  PubMed  Google Scholar 

  31. Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, Hirata K, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M (2002) Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 110:331–340

    CAS  PubMed  Google Scholar 

  32. Pfeifer A, Ruth P, Dostmann W, Sausbier M, Klatt P, Hofmann F (1999) Structure and function of cGMP-dependent protein kinases. Rev Physiol Biochem Pharmacol 135:105–149

    Article  CAS  PubMed  Google Scholar 

  33. Soff GA, Cornwell TL, Cundiff DL, Gately S, Lincoln TM (1997) Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP. J Clin Invest 100:2580–2587

    Article  CAS  PubMed  Google Scholar 

  34. Wolfsgruber W, Feil S, Brummer S, Kuppinger O, Hofmann F, Feil R (2003) A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells. Proc Natl Acad Sci U S A 100:13519–13524

    Article  CAS  PubMed  Google Scholar 

  35. Johnson JL, George SJ, Newby AC, Jackson CL (2005) Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc Natl Acad Sci U S A 102:15575–15580

    Article  CAS  PubMed  Google Scholar 

  36. Luttun A, Lutgens E, Manderveld A, Maris K, Collen D, Carmeliet P, Moons L (2004) Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109:1408–1414

    Article  CAS  PubMed  Google Scholar 

  37. Blaschke F, Takata Y, Caglayan E, Law RE, Hsueh WA (2006) Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. Arterioscler Thromb Vasc Biol 26:28–40

    Article  CAS  PubMed  Google Scholar 

  38. McKnight AJ, Macfarlane AJ, Dri P, Turley L, Willis AC, Gordon S (1996) Molecular cloning of F4/80, a murine macrophage-restricted cell surface glycoprotein with homology to the G-protein-linked transmembrane 7 hormone receptor family. J Biol Chem 271:486–489

    Article  CAS  PubMed  Google Scholar 

  39. Brown EJ (1991) Complement receptors and phagocytosis. Curr Opin Immunol 3:76–82

    Article  CAS  PubMed  Google Scholar 

  40. Douglass TG, Driggers L, Zhang JG, Hoa N, Delgado C, Williams CC, Dan Q, Sanchez R, Jeffes EW, Wepsic HT, Myers MP, Koths K, Jadus MR (2008) Macrophage colony stimulating factor: not just for macrophages anymore! A gateway into complex biologies. Int Immunopharmacol 8:1354–1376

    Article  CAS  PubMed  Google Scholar 

  41. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2:275–281

    Article  CAS  PubMed  Google Scholar 

  42. Hsueh WA, Law RE (2001) PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol 21:1891–1895

    Article  CAS  PubMed  Google Scholar 

  43. Kintsurashvili E, Duka I, Gavras I, Johns C, Farmakiotis D, Gavras H (2001) Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 281:H1778–1783

    CAS  PubMed  Google Scholar 

  44. Fernandes L, Ceravolo GS, Fortes ZB, Tostes R, Santos RA, Santos JA, Mori MA, Pesquero JB, de Carvalho MH (2006) Modulation of kinin B1 receptor expression by endogenous angiotensin II in hypertensive rats. Regul Pept 136:92–97

    Article  CAS  PubMed  Google Scholar 

  45. Mazenot C, Loufrani L, Henrion D, Ribuot C, Müller-Esterl W, Godin-Ribuot D (2001) Endothelial kinin B1-receptors are induced by myocardial ischaemia–reperfusion in the rabbit. J Physiol 530:69–78

    Article  CAS  PubMed  Google Scholar 

  46. Morbidelli L, Parenti A, Giovanelli L, Granger HJ, Ledda F, Ziche M (1998) B1 receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of PGF-2 effects. Br J Pharmacol 124:1286–1292

    Article  CAS  PubMed  Google Scholar 

  47. Chahine R, Adam A, Yamaguchi N, Gaspo R, Regoli D, Nadeau R (1993) Protective effects of bradykinin on the ischemic heart: implication of the B1 receptor. Br J Pharmacol 108:318–322

    CAS  PubMed  Google Scholar 

  48. Lagneux C, Adam A, Lamontagne D (2003) A study of the mediators involved in the protection induced by exogenous kinins in the isolated rat heart. Int Immunopharmacol 3:1511–1518

    Article  CAS  PubMed  Google Scholar 

  49. Hackam DG, Thiruchelvam D, Redelmeier DA (2006) Angiotensin-converting enzyme inhibitors and aortic rupture: a population based case-control study. Lancet 368:659–665

    Article  CAS  PubMed  Google Scholar 

  50. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdos EG (2002) Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem 277:16847–16852

    Article  CAS  PubMed  Google Scholar 

  51. Sabatini RA, Guimarães PB, Fernandes L, Reis FC, Bersanetti PA, Mori MA, Navarro A, Hilzendeger AM, Santos EL, Andrade MC, Chagas JR, Pesquero JL, Casarini DE, Bader M, Carmona AK, Pesquero JB (2008) ACE activity is modulated by kinin B2 receptor. Hypertension 51:689–695

    Article  CAS  PubMed  Google Scholar 

  52. Kaschina E, Stoll M, Sommerfeld M, Steckelings UM, Kreutz R, Unger T (2004) Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. Physiol Genomics 19:41–49

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Adelheid Böttger and Monika Nitz for excellent technical help.

Sources of funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp, 2005/59104-3, 2008/06676-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Deutsche Forschungsgemeinschaft (Ba1374/16-1), by the Deutsche Akademische Austauschdienst/CAPES (PROBRAL), and by the Bundesministerium für Bildung und Forschung/MCT (WTZ program).

Conflict of interest statement

None declared

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to João B. Pesquero.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Merino, V.F., Todiras, M., Mori, M.A. et al. Predisposition to atherosclerosis and aortic aneurysms in mice deficient in kinin B1 receptor and apolipoprotein E. J Mol Med 87, 953–963 (2009). https://doi.org/10.1007/s00109-009-0501-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0501-0

Keywords

Navigation