The online version of this article (doi:10.1186/1758-5996-6-102) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
LX participated in the design of the study, carried out the immunohistochemistry and drafted the manuscript. PZ carried out the animal experiment, RT-PCR, Western blot and performed the statistical analysis. BF conceived of the study, and participated in its design and coordination and helped to draft the manuscript. QQ participated in preparation of AGEs and Western blot. All authors read and approved the final manuscript.
Atorvastatin can downregulate the expression of receptor for advanced glycation end products (RAGE) in the aortas of diabetic rats. However, its effect on healthy rats remains unclear. The aim of this study was to observe the direct impact of atorvastatin on advanced glycation end products- (AGEs) induced RAGE expression in healthy Sprague Dawley (SD) rats.
SD rats received AGE-BSA (20 mg/kg/day or 40 mg/kg/day), dual treatment (AGE-BSA 40 mg/kg/day and atorvastatin 20 mg/kg/day) or no treatment for 12 and 24 weeks, respectively. The deposition of AGEs and expression of RAGE in the animals’ aortas were assessed by Quantitative RT-PCR, immunohistochemistry, and western-blot tests. Serum levels of AGEs were measured using ELISA.
AGE-BSA upregulated the serum level of AGEs, deposition of AGEs, and expression of RAGE in aortas in a time- and dose-dependent way that can accelerate the development and progression of atherosclerosis. These upregulations could be significantly attenuated by atorvastatin in the absence of its lipid-lowering effects. These data provide further evidence for the novo mechanism of atorvastatin’s pleiotropic effect.
Atorvastatin has a direct inhibitory effect on AGEs-RAGE expression in healthy SD rats. These potential pleiotropic vasculoprotective effects are independent of effects on glucose and lipid control.
Authors’ original file for figure 113098_2014_363_MOESM1_ESM.tif
Authors’ original file for figure 213098_2014_363_MOESM2_ESM.tif
Authors’ original file for figure 313098_2014_363_MOESM3_ESM.tif
Authors’ original file for figure 413098_2014_363_MOESM4_ESM.tif
Authors’ original file for figure 513098_2014_363_MOESM5_ESM.tif
Authors’ original file for figure 613098_2014_363_MOESM6_ESM.tif
Ruderman NB, Williamson JR, Brownlee M: Glucose and diabetic vascular disease. FABEB J. 1992, 6: 2905-2914.
Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, De Cuccurullo C, Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A: The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003, 108: 1070-1077. 10.1161/01.CIR.0000086014.80477.0D. CrossRefPubMed
Huttunen HJ, Fages C, Rauvala H: Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999, 274: 19919-19924. 10.1074/jbc.274.28.19919. CrossRefPubMed
Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP: Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes. 2001, 50: 2792-2808. 10.2337/diabetes.50.12.2792. CrossRefPubMed
Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, ASCOT investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003, 361: 1149-1158. 10.1016/S0140-6736(03)12948-0. CrossRefPubMed
Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, Hague W, Beller E, Arulchelvam M, Baker J, Tonkin A, LIPID Study Group: Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care. 2003, 26: 2713-2721. 10.2337/diacare.26.10.2713. CrossRefPubMed
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH, CARDS investigators: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004, 364: 685-696. 10.1016/S0140-6736(04)16895-5. CrossRefPubMed
Davignon J: Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004, 109 (23 Suppl 1): III39-III43. PubMed
Okamoto T, Yamagishi S, Inagaki Y, Amano S, Koga K, Abe R, Takeuchi M, Ohno S, Yoshimura A, Makita Z: Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. FASEB J. 2002, 16: 1928-1930. PubMed
Calkin AC, Giunti C, Sheehy KJ, Chew C, Boolell V, Rajaram YS, Cooper ME, Jandeleit-Dahm KA: The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation,oxidative stress and inflammation. Diabetologia. 2008, 51: 1731-1740. 10.1007/s00125-008-1060-6. CrossRefPubMed
Cuccurullo C, Iezzi A, Fazia ML, De Cesare D, Di Francesco A, Muraro R, Bei R, Ucchino S, Spigonardo F, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A, Cipollone F: Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2006, 26: 2716-2723. 10.1161/01.ATV.0000249630.02085.12. CrossRefPubMed
Kilhovd BK, Juutilainen A, Lehto S, Rönnemaa T, Torjesen PA, Birkeland KI, Berg TJ, Hanssen KF, Laakso M: High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic Men. A population-based 18-year follow-up study. Arterioscler Thromb Vasc Biol. 2005, 25: 815-820. 10.1161/01.ATV.0000158380.44231.fe. CrossRefPubMed
Yamagishi S, Imaizumi T: Diabetic vascular complications:pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm. 2005, 11: 2279-2299. 10.2174/1381612054367300. CrossRef
Stolf AM, Lívero Fdos R, Dreifuss AA, Bastos-Pereira AL, Fabosi IA, de Souza CE A, Gomes Lde O, Chicorski R, Brandt AP, Cadena SM, Telles JE, Hauser AB, Elferink RO, Zampronio AR, Acco A: Effects of statins on liver cell function and inflammation in septic rats. J Surg Res. 2012, 178: 888-897. 10.1016/j.jss.2012.08.019. CrossRefPubMed
Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O’Leary DH, Genuth S, Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group: Diabetes control and complications trial, epidemiology of diabetes interventions and complications research group: intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003, 348: 2294-2303. CrossRefPubMed
Cipollone F, Fazia M, Iezzi A, Zucchelli M, Pini B, De Cesare D, Ucchino S, Spigonardo F, Bajocchi G, Bei R, Muraro R, Artese L, Piattelli A, Chiarelli F, Cuccurullo F, Mezzetti A: Suppression of the functionally coupled cyclooxygenase- 2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans. Circulation. 2003, 107: 1479-1485. 10.1161/01.CIR.0000056530.03783.81. CrossRefPubMed
Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J: Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001, 103: 926-933. 10.1161/01.CIR.103.7.926. CrossRefPubMed
de la Maza MP, Uribarri J, Olivares D, Hirsch S, Leiva L, Barrera G, Bunout D: Weight increase is associated with skeletal muscle immunostaining for advanced glycation end products, receptor for advanced glycation end products, and oxidation injury. Rejuvenation Res. 2008, 11: 1041-1048. 10.1089/rej.2008.0786. CrossRefPubMed
- Atorvastatin inhibits the expression of RAGE induced by advanced glycation end products on aortas in healthy Sprague–Dawley rats
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II