Skip to main content

Advertisement

SpringerLink
Log in

Pioglitazone attenuates progression of aortic valve calcification via down-regulating receptor for advanced glycation end products

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Receptor for advanced glycation end products (RAGE) is associated with inflammation and the progression of cardiovascular diseases. The current study tested the hypothesis that RAGE is involved in the pathogenesis of aortic valve (AV) calcification. Pioglitazone attenuated AV calcification in experimental hypercholesterolemic rabbits via down-regulation of RAGE. Male New Zealand rabbits weighing 2.5–3.0 kg were randomly divided into three groups: control group, high cholesterol + vitamin D2 (HC + vitD2) group and HC + vitD2 supplemented with pioglitazone group. Compared with HC + vitD2 group, pioglitazone significantly inhibited the progression of AV calcification assessed by echocardiography. HC + vitD2 diet markedly increased RAGE expression, oxidative stress, inflammatory cells infiltration and osteopontin expression. These changes were also significantly attenuated by administration of pioglitazone. Cultured porcine aortic valve interstitial cells (VICs) were used as in vitro model. We found that advanced glycation end products of bovine serum albumin markedly increased the expression of RAGE, induced high levels of production of pro-inflammatory cytokines and promoted osteoblastic differentiation of VICs. However, these effects were found to be remarkably suppressed by siRNA silencing of RAGE and pioglitazone as well. Our data provide evidence that RAGE activation-induced inflammation promotes AV calcification in hypercholesterolemic rabbits, which can be attenuated by pioglitazone treatment. This beneficial effect is associated with remarkable down-regulation of RAGE expression.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, Cheng SL, Towler DA (2007) Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr−/− mice. Arterioscler Thromb Vasc Biol 27:2589–2596. doi:10.1161/ATVBAHA.107.153668

    Article  PubMed  CAS  Google Scholar 

  2. Basta G, Corciu AI, Vianello A, Del Turco S, Foffa I, Navarra T, Chiappino D, Berti S, Mazzone A (2010) Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis. Atherosclerosis 210:614–618. doi:10.1016/j.atherosclerosis.2009.12.029

    Article  PubMed  CAS  Google Scholar 

  3. Beckmann E, Grau JB, Sainger R, Poggio P, Ferrari G (2010) Insights into the use of biomarkers in calcific aortic valve disease. J Heart Valve Dis 19:441–452

    PubMed  Google Scholar 

  4. Birnbaum Y, Long B, Qian J, Perez-Polo JR, Ye Y (2011) Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-gamma-independent manner. Basic Res Cardiol 106:431–446. doi:10.1007/s00395-011-0162-3

    Article  PubMed  CAS  Google Scholar 

  5. Bonow RO, Carabello BA, Chatterjee K, De Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS (2008) 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American college of Cardiology/American heart association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease): endorsed by the society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, and society of thoracic surgeons. Circulation 118:e523–e661. doi:10.1161/CIRCULATIONAHA.108.190748

    Article  PubMed  Google Scholar 

  6. Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A, Migheli A, Stern D (1993) Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 143:1699–1712

    PubMed  CAS  Google Scholar 

  7. Cai Z, Li F, Peng C, Li H, Zong Y, Liu Z, Qu S (2010) Effect of insulin on the differential expression of VLDL receptor isoforms of SGC7901 cell and its biological implication. J Huazhong Univ Sci Technol Med Sci 30:551–555. doi:10.1007/s11596-010-0541-2

    Article  PubMed  CAS  Google Scholar 

  8. Cecil DL, Terkeltaub RA (2011) Arterial calcification is driven by RAGE in Enpp 1−/− mice. J Vasc Res 48:227–235. doi:10.1159/000318805

    Article  PubMed  CAS  Google Scholar 

  9. Chavakis T, Bierhaus A, Nawroth PP (2004) RAGE (receptor for advanced glycation end products): a central player in the inflammatory response. Microbes Infect 6:1219–1225. doi:10.1016/j.micinf.2004.08.004

    Article  PubMed  CAS  Google Scholar 

  10. Drolet MC, Arsenault M, Couet J (2003) Experimental aortic valve stenosis in rabbits. J Am Coll Cardiol 41:1211–1217

    Article  PubMed  Google Scholar 

  11. Gallagher AM, Smeeth L, Seabroke S, Leufkens HG, van Staa TP (2011) Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data. PLoS ONE 6:e28157. doi:10.1371/journal.pone.0028157

    Article  PubMed  CAS  Google Scholar 

  12. Hanefeld M, Pfutzner A, Forst T, Kleine I, Fuchs W (2011) Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study. Cardiovasc Diabetol 10:65. doi:10.1186/1475-2840-10-65

    Article  PubMed  CAS  Google Scholar 

  13. Harja E, Bu DX, Hudson BI, Chang JS, Shen X, Hallam K, Kalea AZ, Lu Y, Rosario RH, Oruganti S, Nikolla Z, Belov D, Lalla E, Ramasamy R, Yan SF, Schmidt AM (2008) Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J Clin Invest 118:183–194. doi:10.1172/JCI32703

    Article  PubMed  CAS  Google Scholar 

  14. Helske S, Lindstedt KA, Laine M, Mayranpaa M, Werkkala K, Lommi J, Turto H, Kupari M, Kovanen PT (2004) Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 44:1859–1866. doi:10.1016/j.jacc.2004.07.054

    Article  PubMed  CAS  Google Scholar 

  15. Hernandez AV, Usmani A, Rajamanickam A, Moheet A (2011) Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs 11:115–128. doi:10.2165/11587580-000000000-00000

    Article  PubMed  CAS  Google Scholar 

  16. Hofmann Bowman MA, Gawdzik J, Bukhari U, Husain AN, Toth PT, Kim G, Earley J, McNally EM (2011) S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol 31:337–344. doi:10.1161/ATVBAHA.110.217745

    Article  PubMed  CAS  Google Scholar 

  17. Hsueh WA, Bruemmer D (2004) Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. Hypertension 43:297–305. doi:10.1161/01.HYP.0000113626.76571.5b

    Article  PubMed  CAS  Google Scholar 

  18. Ihm SH, Chang K, Kim HY, Baek SH, Youn HJ, Seung KB, Kim JH (2010) Peroxisome proliferator-activated receptor-gamma activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor. Basic Res Cardiol 105:399–407. doi:10.1007/s00395-009-0071-x

    Article  PubMed  CAS  Google Scholar 

  19. Johnson CM, Hanson MN, Helgeson SC (1987) Porcine cardiac valvular subendothelial cells in culture: cell isolation and growth characteristics. J Mol Cell Cardiol 19:1185–1193

    Article  PubMed  CAS  Google Scholar 

  20. Joner M, Farb A, Cheng Q, Finn AV, Acampado E, Burke AP, Skorija K, Creighton W, Kolodgie FD, Gold HK, Virmani R (2007) Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-beta and MCP-1. Arterioscler Thromb Vasc Biol 27:182–189. doi:10.1161/01.ATV.0000251021.28725.e8

    Article  PubMed  CAS  Google Scholar 

  21. Kaden JJ, Bickelhaupt S, Grobholz R, Vahl CF, Hagl S, Brueckmann M, Haase KK, Dempfle CE, Borggrefe M (2004) Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis 13:560–566

    PubMed  Google Scholar 

  22. Kaden JJ, Dempfle CE, Grobholz R, Fischer CS, Vocke DC, Kilic R, Sarikoc A, Pinol R, Hagl S, Lang S, Brueckmann M, Borggrefe M (2005) Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol 14:80–87. doi:10.1016/j.carpath.2005.01.002

    Article  PubMed  CAS  Google Scholar 

  23. Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, Brueckmann M, Vahl C, Hagl S, Haase KK, Borggrefe M (2003) Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis 170:205–211

    Article  PubMed  CAS  Google Scholar 

  24. Katz R, Budoff MJ, Takasu J, Shavelle DM, Bertoni A, Blumenthal RS, Ouyang P, Wong ND, O’Brien KD (2009) Relationship of metabolic syndrome with incident aortic valve calcium and aortic valve calcium progression: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes 58:813–819. doi:10.2337/db08-1515

    Article  PubMed  CAS  Google Scholar 

  25. Liberman M, Bassi E, Martinatti MK, Lario FC, Wosniak J Jr, Pomerantzeff PM, Laurindo FR (2008) Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification. Arterioscler Thromb Vasc Biol 28:463–470. doi:10.1161/ATVBAHA.107.156745

    Article  PubMed  CAS  Google Scholar 

  26. Lin L (2006) RAGE on the Toll Road? Cell Mol Immunol 3:351–358

    PubMed  CAS  Google Scholar 

  27. Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci 14:1403–1413

    Article  PubMed  CAS  Google Scholar 

  28. Loke YK, Kwok CS, Singh S (2011) Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 342:d1309. doi:10.1136/bmj.d1309

    Article  PubMed  Google Scholar 

  29. Lu Y, Qin W, Shen T, Dou L, Man Y, Wang S, Xiao C, Li J (2011) The antioxidant N-acetylcysteine promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-kappaB in ApoE-deficient mice. J Atheroscler Thromb 18:998–1008

    Article  PubMed  CAS  Google Scholar 

  30. Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, Balkwill FR, Tuveson DA, Hagemann T (2011) Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Invest 121:4685–4699. doi:10.1172/JCI45797

    Article  PubMed  CAS  Google Scholar 

  31. Marx N, Walcher D, Ivanova N, Rautzenberg K, Jung A, Friedl R, Hombach V, de Caterina R, Basta G, Wautier MP, Wautiers JL (2004) Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes 53:2662–2668

    Article  PubMed  CAS  Google Scholar 

  32. Nagy E, Andersson DC, Caidahl K, Eriksson MJ, Eriksson P, Franco-Cereceda A, Hansson GK, Back M (2011) Upregulation of the 5-lipoxygenase pathway in human aortic valves correlates with severity of stenosis and leads to leukotriene-induced effects on valvular myofibroblasts. Circulation 123:1316–1325. doi:10.1161/CIRCULATIONAHA.110.966846

    Article  PubMed  CAS  Google Scholar 

  33. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004

    PubMed  CAS  Google Scholar 

  34. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M (2006) Burden of valvular heart diseases: a population-based study. Lancet 368:1005–1011. doi:10.1016/S0140-6736(06)69208-8

    Article  PubMed  Google Scholar 

  35. O’Brien KD (2006) Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more). Arterioscler Thromb Vasc Biol 26:1721–1728. doi:10.1161/01.ATV.0000227513.13697.ac

    Article  PubMed  Google Scholar 

  36. Olsson M, Dalsgaard CJ, Haegerstrand A, Rosenqvist M, Ryden L, Nilsson J (1994) Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol 23:1162–1170

    Article  PubMed  CAS  Google Scholar 

  37. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD (1994) Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation 90:844–853

    Article  PubMed  CAS  Google Scholar 

  38. Prince M, Banerjee C, Javed A, Green J, Lian JB, Stein GS, Bodine PV, Komm BS (2001) Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. J Cell Biochem 80:424–440. doi:10.1002/1097-4644(20010301)80:3<424

    Article  PubMed  CAS  Google Scholar 

  39. Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O’Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM (2011) Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation 124:1783–1791. doi:10.1161/CIRCULATIONAHA.110.006767

    Article  PubMed  Google Scholar 

  40. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79–82. doi:10.1038/34178

    Article  PubMed  CAS  Google Scholar 

  41. Soro-Paavonen A, Watson AM, Li J, Paavonen K, Koitka A, Calkin AC, Barit D, Coughlan MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA (2008) Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57:2461–2469. doi:10.2337/db07-1808

    Article  PubMed  CAS  Google Scholar 

  42. Speidl WS, Cimmino G, Ibanez B, Elmariah S, Hutter R, Garcia MJ, Fuster V, Goldman ME, Badimon JJ (2010) Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model. Eur Heart J 31:2049–2057. doi:10.1093/eurheartj/ehq064

    Article  PubMed  CAS  Google Scholar 

  43. Suga T, Iso T, Shimizu T, Tanaka T, Yamagishi S, Takeuchi M, Imaizumi T, Kurabayashi M (2011) Activation of receptor for advanced glycation end products induces osteogenic differentiation of vascular smooth muscle cells. J Atheroscler Thromb 18:670–683

    Article  PubMed  CAS  Google Scholar 

  44. Sun L, Ishida T, Yasuda T, Kojima Y, Honjo T, Yamamoto Y, Yamamoto H, Ishibashi S, Hirata K, Hayashi Y (2009) RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovasc Res 82:371–381. doi:10.1093/cvr/cvp036

    Article  PubMed  CAS  Google Scholar 

  45. Syvaranta S, Helske S, Laine M, Lappalainen J, Kupari M, Mayranpaa MI, Lindstedt KA, Kovanen PT (2010) Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-perpetuating angiogenic pathway in aortic valve stenosis. Arterioscler Thromb Vasc Biol 30:1220–1227. doi:10.1161/ATVBAHA.109.198267

    Article  PubMed  CAS  Google Scholar 

  46. Tanikawa T, Okada Y, Tanikawa R, Tanaka Y (2009) Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res 46:572–580. doi:10.1159/000226225

    Article  PubMed  CAS  Google Scholar 

  47. Volz HC, Laohachewin D, Seidel C, Lasitschka F, Keilbach K, Wienbrandt AR, Andrassy J, Bierhaus A, Kaya Z, Katus HA, Andrassy M (2012) S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-kappaB signaling. Basic Res Cardiol 107:250. doi:10.1007/s00395-012-0250-z

    Article  PubMed  Google Scholar 

  48. Volz HC, Seidel C, Laohachewin D, Kaya Z, Muller OJ, Pleger ST, Lasitschka F, Bianchi ME, Remppis A, Bierhaus A, Katus HA, Andrassy M (2010) HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol 105:805–820. doi:10.1007/s00395-010-0114-3

    Article  PubMed  CAS  Google Scholar 

  49. Wang K, Zhou Z, Zhang M, Fan L, Forudi F, Zhou X, Qu W, Lincoff AM, Schmidt AM, Topol EJ, Penn MS (2006) Peroxisome proliferator-activated receptor gamma down-regulates receptor for advanced glycation end products and inhibits smooth muscle cell proliferation in a diabetic and nondiabetic rat carotid artery injury model. J Pharmacol Exp Ther 317:37–43. doi:10.1124/jpet.105.095125

    Article  PubMed  CAS  Google Scholar 

  50. Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y (2011) The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury. Basic Res Cardiol 106:925–952. doi:10.1007/s00395-011-0216-6

    Article  PubMed  CAS  Google Scholar 

  51. Yu Z, Seya K, Daitoku K, Motomura S, Fukuda I, Furukawa K (2011) Tumor necrosis factor-alpha accelerates the calcification of human aortic valve interstitial cells obtained from patients with calcific aortic valve stenosis via the BMP2-Dlx5 pathway. J Pharmacol Exp Ther 337:16–23. doi:10.1124/jpet.110.177915

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was funded by grants from the National Natural Science Foundation of China (81170214) and “863” Program (2009AA03Z420). We specially appreciate the great help with echocardiography from Dr. Xiaojun Bi.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, 430022, China

    Fei Li, Xucong Shi, Qiao Zhang, Si Chen, Jiawei Shi & Nianguo Dong

  2. Department of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China

    Zhejun Cai & Dao Wen Wang

  3. Department of Cardiology, Second Affiliated Hospital, Medical College, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, China

    Zhejun Cai

  4. Department of Cardiology, Henan Provincial People’s Hospital, 7 Weiwu Road, Zhengzhou, 450000, China

    Fang Chen

Authors
  1. Fei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhejun Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xucong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Si Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiawei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dao Wen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nianguo Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dao Wen Wang or Nianguo Dong.

Additional information

F. Li and Z. Cai contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 727 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, F., Cai, Z., Chen, F. et al. Pioglitazone attenuates progression of aortic valve calcification via down-regulating receptor for advanced glycation end products. Basic Res Cardiol 107, 306 (2012). https://doi.org/10.1007/s00395-012-0306-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-012-0306-0

Keywords

Search

Navigation