Skip to main content
SpringerLink
Log in

Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Recently, we reported an elevated level of glucose-generated carbonyl adducts on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in hearts of streptozotocin(STZ)-induced diabetic rats. We also showed these adduct impaired RyR2 and SERCA2 activities, and altered evoked Ca2+ transients. What is less clear is if lipid-derived malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) also chemically react with and impair RyR2 and SERCA2 activities in diabetes? This study used western blot assays with adduct-specific antibodies and confocal microscopy to assess levels of MDA, 4-HNE, N ε-carboxy(methyl)lysine (CML), pentosidine, and pyrraline adducts on RyR2 and SERCA2 and evoked intracellular transient Ca2+ kinetics in myocytes from control, diabetic, and treated-diabetic rats. MDA and 4-HNE adducts were not detected on RyR2 and SERCA2 from either control or 8 weeks diabetic rats with altered evoked Ca2+ transients. However, CML, pentosidine, and pyrraline adducts were elevated three- to five-fold (p < 0.05). Treating diabetic rats with pyridoxamine (a scavenger of reactive carbonyl species, RCS) or aminoguanidine (a mixed reactive oxygen species-RCS scavenger) reduced CML, pentosidine, and pyrraline adducts on RyR2 and SERCA2 and blunted SR Ca2+ cycling changes. Treating diabetic rats with the superoxide dismutase mimetic tempol had no impact on MDA and 4-HNE adducts on RyR2 and SERCA2, and on SR Ca2+ cycling. From these data we conclude that lipid-derived MDA and 4-HNE adducts are not formed on RyR2 and SERCA2 in this model of diabetes, and are therefore unlikely to be directly contributing to the SR Ca2+ dysregulation.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. American Diabetes A (2008) Economic costs of diabetes in the U.S. in 2007. Diabetes Care 31:596–615. doi:10.2337/dc08-9017

    Article  Google Scholar 

  2. Giorda CB, Manicardi V, Diago Cabezudo J (2011) The impact of diabetes mellitus on healthcare costs in Italy. Expert Rev Pharmacoecon Outcomes Res 11:709–719. doi:10.1586/erp.11.78

    Article  PubMed  Google Scholar 

  3. Nosadini R, Tonolo G (2002) Cardiovascular and renal protection in type 2 diabetes mellitus: the role of calcium channel blockers. J Am Soc Nephrol 13(Suppl 3):S216–S223

    Article  PubMed  CAS  Google Scholar 

  4. Battiprolu PK, Gillette TG, Wang ZV, Lavandero S, Hill JA (2010) Diabetic cardiomyopathy: mechanisms and therapeutic targets. Drug Discov Today Dis Mech 7:e135–e143. doi:10.1016/j.ddmec.2010.08.001

    Article  PubMed  CAS  Google Scholar 

  5. Thandavarayan RA, Giridharan VV, Watanabe K, Konishi T (2011) Diabetic cardiomyopathy and oxidative stress: role of antioxidants. Cardiovasc Hematol Agents Med Chem 9(4):225–230

    Google Scholar 

  6. Boudina S, Abel ED (2010) Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11:31–39. doi:10.1007/s11154-010-9131-7

    Article  PubMed  Google Scholar 

  7. Duncan JG (2011) Mitochondrial dysfunction in diabetic cardiomyopathy. Biochim Biophys Acta 1813:1351–1359. doi:10.1016/j.bbamcr.2011.01.014

    Article  PubMed  CAS  Google Scholar 

  8. D’Souza A, Howarth FC, Yanni J, Dobryznski H, Boyett MR, Adeghate E, Bidasee KR, Singh J (2011) Left ventricle structural remodelling in the prediabetic Goto-Kakizaki rat. Exp Physiol 96:875–888. doi:10.1113/expphysiol.2011.058271

    PubMed  Google Scholar 

  9. Shao C, Tian C, Ouyang S, Moore C, Alomar F, Nemet I, D’Souza A, Nagai R, Kutty S, Rozanski GJ, Ramanadham S, Singh J, Bidasee K (2012) Carbonylation induces heterogeneity in cardiac ryanodine receptors (RyR2) function during diabetes. Mol Pharmacol 82(3):383–399. doi:10.1124/mol.112.078352

    Article  PubMed  CAS  Google Scholar 

  10. Shao CH, Capek HL, Patel KP, Wang M, Tang K, DeSouza C, Nagai R, Mayhan W, Periasamy M, Bidasee KR (2011) Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes. Diabetes 60:947–959. doi:10.2337/db10-1145

    Article  PubMed  CAS  Google Scholar 

  11. Taha M, Lopaschuk GD (2007) Alterations in energy metabolism in cardiomyopathies. Ann Med 39:594–607. doi:10.1080/07853890701618305

    Article  PubMed  CAS  Google Scholar 

  12. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223. doi:10.1161/CIRCULATIONAHA.106.679597

    Article  PubMed  Google Scholar 

  13. Stanley WC, Lopaschuk GD, McCormack JG (1997) Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 34:25–33

    Article  PubMed  CAS  Google Scholar 

  14. Kota SK, Kota SK, Jammula S, Panda S, Modi KD (2011) Effect of diabetes on alteration of metabolism in cardiac myocytes: therapeutic implications. Diabetes Technol Ther 13:1155–1160. doi:10.1089/dia.2011.0120

    Article  PubMed  CAS  Google Scholar 

  15. Wright JJ, Kim J, Buchanan J, Boudina S, Sena S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kandror KV, Abel ED (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc Res 82:351–360. doi:10.1093/cvr/cvp017

    Article  PubMed  CAS  Google Scholar 

  16. Munzel T, Gori T, Bruno RM, Taddei S (2010) Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 31:2741–2748. doi:10.1093/eurheartj/ehq396

    Article  PubMed  Google Scholar 

  17. Tousoulis D, Briasoulis A, Papageorgiou N, Tsioufis C, Tsiamis E, Toutouzas K, Stefanadis C (2011) Oxidative stress and endothelial function: therapeutic interventions. Recent Pat Cardiovasc Drug Discov 6:103–114

    Article  PubMed  CAS  Google Scholar 

  18. Marjani A (2010) Lipid peroxidation alterations in type 2 diabetic patients. Pak J Biol Sci 13:723–730

    Article  PubMed  CAS  Google Scholar 

  19. Piconi L, Quagliaro L, Ceriello A (2003) Oxidative stress in diabetes. Clin Chem Lab Med 41:1144–1149. doi:10.1515/CCLM.2003.177

    Article  PubMed  CAS  Google Scholar 

  20. Uchida K (2000) Role of reactive aldehyde in cardiovascular diseases. Free Radic Biol Med 28:1685–1696

    Article  PubMed  CAS  Google Scholar 

  21. Basu S (2004) Isoprostanes: novel bioactive products of lipid peroxidation. Free Radic Res 38:105–122

    Article  PubMed  CAS  Google Scholar 

  22. Dirkx E, Schwenk RW, Glatz JF, Luiken JJ, van Eys GJ (2011) High fat diet induced diabetic cardiomyopathy. Prostaglandins Leukot Essent Fatty Acids 85:219–225. doi:10.1016/j.plefa.2011.04.018

    Article  PubMed  CAS  Google Scholar 

  23. Slatter DA, Bolton CH, Bailey AJ (2000) The importance of lipid-derived malondialdehyde in diabetes mellitus. Diabetologia 43:550–557. doi:10.1007/s001250051342

    Article  PubMed  CAS  Google Scholar 

  24. Voulgaridou GP, Anestopoulos I, Franco R, Panayiotidis MI, Pappa A (2011) DNA damage induced by endogenous aldehydes: current state of knowledge. Mutat Res 711:13–27. doi:10.1016/j.mrfmmm.2011.03.006

    Article  PubMed  CAS  Google Scholar 

  25. Shao CH, Rozanski GJ, Patel KP, Bidasee KR (2007) Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats. J Mol Cell Cardiol 42:234–246. doi:10.1016/j.yjmcc.2006.08.018

    Article  PubMed  CAS  Google Scholar 

  26. Troncoso Brindeiro CM, Lane PH, Carmines PK (2012) Tempol prevents altered K(+) channel regulation of afferent arteriolar tone in diabetic rat kidney. Hypertension 59:657–664. doi:10.1161/HYPERTENSIONAHA.111.184218

    Article  PubMed  CAS  Google Scholar 

  27. Wilcox CS (2010) Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther 126:119–145. doi:10.1016/j.pharmthera.2010.01.003

    Article  PubMed  CAS  Google Scholar 

  28. Shao CH, Rozanski GJ, Nagai R, Stockdale FE, Patel KP, Wang M, Singh J, Mayhan WG, Bidasee KR (2010) Carbonylation of myosin heavy chains in rat heart during diabetes. Biochem Pharmacol 80:205–217. doi:10.1016/j.bcp.2010.03.024

    Article  PubMed  CAS  Google Scholar 

  29. Dai S, Fraser H, Yuen VG, McNeill JH (1994) Improvement in cardiac function in streptozotocin-diabetic rats by salt loading. Can J Physiol Pharmacol 72:1288–1293

    Article  PubMed  CAS  Google Scholar 

  30. Shao CH, Wehrens XH, Wyatt TA, Parbhu S, Rozanski GJ, Patel KP, Bidasee KR (2009) Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol 106:1280–1292. doi:10.1152/japplphysiol.91280.2008

    Article  PubMed  CAS  Google Scholar 

  31. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr (2004) Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 27:699–703

    Article  PubMed  Google Scholar 

  32. Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW, Guatimosim S, Lederer WJ, Matlib MA (2002) Defective intracellular Ca(2+) signaling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol Heart Circ Physiol 283:H1398–H1408. doi:10.1152/ajpheart.00313.2002

    PubMed  CAS  Google Scholar 

  33. Belke DD, Dillmann WH (2004) Altered cardiac calcium handling in diabetes. Curr Hypertens Rep 6:424–429

    Article  PubMed  Google Scholar 

  34. Bidasee KR, Dincer UD, Besch HR Jr (2001) Ryanodine receptor dysfunction in hearts of streptozotocin-induced diabetic rats. Mol Pharmacol 60:1356–1364

    PubMed  CAS  Google Scholar 

  35. Ferrington DA, Krainev AG, Bigelow DJ (1998) Altered turnover of calcium regulatory proteins of the sarcoplasmic reticulum in aged skeletal muscle. J Biol Chem 273:5885–5891

    Article  PubMed  CAS  Google Scholar 

  36. Bidasee KR, Nallani K, Besch HR Jr, Dincer UD (2003) Streptozotocin-induced diabetes increases disulfide bond formation on cardiac ryanodine receptor (RyR2). J Pharmacol Exp Ther 305:989–998. doi:10.1124/jpet.102.046201

    Article  PubMed  CAS  Google Scholar 

  37. Shah G, Pinnas JL, Lung CC, Mahmoud S, Mooradian AD (1994) Tissue-specific distribution of malondialdehyde modified proteins in diabetes mellitus. Life Sci 55:1343–1349

    Article  PubMed  CAS  Google Scholar 

  38. Minamiyama Y, Bito Y, Takemura S, Takahashi Y, Kodai S, Mizuguchi S, Nishikawa Y, Suehiro S, Okada S (2007) Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats. J Pharmacol Exp Ther 320:535–543. doi:10.1124/jpet.106.110460

    Article  PubMed  CAS  Google Scholar 

  39. Zhang Y, Babcock SA, Hu N, Maris JR, Wang H, Ren J (2012) Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3beta and mitochondrial function. BMC Med 10:40. doi:10.1186/1741-7015-10-40

    Article  PubMed  CAS  Google Scholar 

  40. Agadjanyan ZS, Dmitriev LF, Dugin SF (2005) A new role of phosphoglucose isomerase. Involvement of the glycolytic enzyme in aldehyde metabolism. Biochemistry (Mosc) 70:1251–1255

    Article  CAS  Google Scholar 

  41. Thornalley PJ (1990) The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J 269:1–11

    PubMed  CAS  Google Scholar 

  42. Iwata K, Nishinaka T, Matsuno K, Kakehi T, Katsuyama M, Ibi M, Yabe-Nishimura C (2007) The activity of aldose reductase is elevated in diabetic mouse heart. J Pharmacol Sci 103:408–416

    Article  PubMed  CAS  Google Scholar 

  43. Choudhary S, Xiao T, Srivastava S, Zhang W, Chan LL, Vergara LA, Van Kuijk FJ, Ansari NH (2005) Toxicity and detoxification of lipid-derived aldehydes in cultured retinal pigmented epithelial cells. Toxicol Appl Pharmacol 204:122–134. doi:10.1016/j.taap.2004.08.023

    Article  PubMed  CAS  Google Scholar 

  44. Shi Z, Chen AD, Xu Y, Chen Q, Gao XY, Wang W, Zhu GQ (2009) Long-term administration of tempol attenuates postinfarct ventricular dysfunction and sympathetic activity in rats. Pflugers Arch 458:247–257. doi:10.1007/s00424-008-0627-x

    Article  PubMed  CAS  Google Scholar 

  45. Matsumoto K, Krishna MC, Mitchell JB (2004) Novel pharmacokinetic measurement using electron paramagnetic resonance spectroscopy and simulation of in vivo decay of various nitroxyl spin probes in mouse blood. J Pharmacol Exp Ther 310:1076–1083. doi:10.1124/jpet.104.066647

    Article  PubMed  CAS  Google Scholar 

  46. Grote K, Flach I, Luchtefeld M, Akin E, Holland SM, Drexler H, Schieffer B (2003) Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res 92:e80–e86. doi:10.1161/01.RES.0000077044.60138.7C

    Article  PubMed  CAS  Google Scholar 

  47. Zhao W, Zhao T, Chen Y, Ahokas RA, Sun Y (2008) Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem 317:43–50. doi:10.1007/s11010-008-9803-8

    Article  PubMed  CAS  Google Scholar 

  48. Voziyan PA, Hudson BG (2005) Pyridoxamine: the many virtues of a maillard reaction inhibitor. Ann N Y Acad Sci 1043:807–816. doi:10.1196/annals.1333.093

    Article  PubMed  CAS  Google Scholar 

  49. Thornalley PJ (2003) Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys 419:31–40

    Article  PubMed  CAS  Google Scholar 

  50. Sansbury BE, Riggs DW, Brainard RE, Salabei JK, Jones SP, Hill BG (2011) Responses of hypertrophied myocytes to reactive species: implications for glycolysis and electrophile metabolism. Biochem J 435:519–528. doi:10.1042/BJ20101390

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Janice A. Taylor and James R. Talaska of the Confocal Laser Scanning Microscope Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy. This work was supported in part by grants from the Edna Ittner Research Foundation, American Diabetes Association [1-06-RA-11] and the National Institutes of Health [HL085061].

Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, 985800 Nebraska Medical Center, Durham Research Center, DRC 3047, Omaha, NE, 68198-5800, USA

    Caronda J. Moore, Chun Hong Shao & Keshore R. Bidasee

  2. Laboratory of Food and Regulation Biology, Department of Biosciences, School of Agriculture, Tokai University, Tokyo, Japan

    Ryoji Nagai

  3. Joint Division of Pediatric Cardiology, University of Nebraska/Creighton University and Children’s Hospital and Medical Center, Omaha, NE, USA

    Shelby Kutty

  4. School of Forensic and Investigative Sciences and School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK

    Jaipaul Singh

  5. Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Keshore R. Bidasee

  6. N146 Beadle Center, Nebraska Center for Redox Biology, Lincoln, NE, 68588-0662, USA

    Keshore R. Bidasee

Authors
  1. Caronda J. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chun Hong Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryoji Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shelby Kutty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaipaul Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keshore R. Bidasee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keshore R. Bidasee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moore, C.J., Shao, C.H., Nagai, R. et al. Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes. Mol Cell Biochem 376, 121–135 (2013). https://doi.org/10.1007/s11010-013-1558-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1558-1

Keywords

Search

Navigation