Abstract
Efficient and rhythmic cardiac contractions depend critically on the adequate and synchronized release of Ca2+ from the sarcoplasmic reticulum (SR) via ryanodine receptor Ca2+ release channels (RyR2) and its reuptake via sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a). It is well established that this orchestrated process becomes compromised in diabetes. What remain incompletely defined are the molecular mechanisms responsible for the dysregulation of RyR2 and SERCA2a in diabetes. Earlier, we found elevated levels of carbonyl adducts on RyR2 and SERCA2a isolated from hearts of type 1 diabetic rats and showed the presence of these posttranslational modifications compromised their functions. We also showed that these mono- and di-carbonyl reactive carbonyl species (RCS) do not indiscriminately react with all basic amino acid residues on RyR2 and SERCA2a; some residues are more susceptible to carbonylation (modification by RCS) than others. A key unresolved question in the field is which of the many RCS that are upregulated in the heart in diabetes chemically react with RyR2 and SERCA2a? This brief review introduces readers to the field of RCS and their roles in perturbing SR Ca2+ cycling in diabetes. It also provides new experimental evidence that not all RCS that are upregulated in the heart in diabetes chemically react with RyR2 and SERCA2a, methylglyoxal and glyoxal preferentially do.
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References
American Diabetes Association. Living with diabetes: complications. http://www.diabetes.org/living-with-diabetes/complications/. Accessed 6 Nov 2012
American Diabetes Association (2008) Economic costs of diabetes, in the US in 2007. Diabetes Care 31(3):596–615
Diabetes SchernthanerG, Disease Cardiovascular (2010) Is intensive glucose control beneficial or deadly? Lessons from ACCORD, ADVANCE, VADT, UKPDS, PROactive, and NICE-SUGAR. Wien Med Wochenschr 160(1–2):8–19
Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, Zimmet P, Son HY (2006) Epidemic obesity and type 2 diabetes in Asia. Lancet 368:1681–1688
The DCCT Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986
UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589
Genuth S (2008) The UKPDS and its global impact. Diabet Med 25(Suppl 2):57–62
ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byingto RP, Rosenberg YD, Friedewald WT (2011) Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 364(9):818–828
Gerstein HC, Miller ME, Byington RP et al (2008) Action to control cardiovascular risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559
Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49
Lehnart SE, Wehrens XH, Kushnir A, Marks AR (2004) Cardiac ryanodine receptor function and regulation in heart disease. Ann NY Acad Sci 1015:144–159
Watanabe H, Knollmann BC (2011) Mechanism underlying catecholaminergic polymorphic ventricular tachycardia and approaches to therapy. J Electrocardiol 44(6):650–655
Yano M, Yamamoto T, Kobayashi S, Matsuzaki M (2009) Role of ryanodine receptor as a Ca²(+) regulatory center in normal and failing hearts. J Cardiol 53(1):1–7
Lehnart SE, Schillinger W, Pieske B, Prestle J, Just H, Hasenfuss G (1998) Sarcoplasmic reticulum proteins in heart failure. Ann NY Acad Sci 853:220–230
Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473(7348):528–531
Park SW, Zhou Y, Lee J, Lee J, Ozcan U (2010) Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci USA 107(45):19320–19325
Ren J, Davidoff AJ (1997) Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol 272(1 Pt 2):H148–H158
Zhong Y, Ahmed S, Grupp IL, Matlib MA (2001) Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts. Am J Physiol Heart Circ Physiol 281(3):H1137–H1147
Lacombe VA, Viatchenko-Karpinski S, Terentyev D, Sridhar A, Emani S, Bonagura JD, Feldman DS, Györke S, Carnes CA (2007) Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol 293(5):R1787–R1797
Ligeti L, Szenczi O, Prestia CM, Szabó C, Horváth K, Marcsek ZL, van Stiphout RG, van Riel NA, Op den Buijs J, Van der Vusse GJ, Ivanics T (2006) Altered calcium handling is an early sign of streptozotocin-induced diabetic cardiomyopathy. Int J Mol Med 17(6):1035–1043
Pereira L, Matthes J, Schuster I, Valdivia HH, Herzig S, Richard S, Gómez AM (2006) Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55(3):608–615
Yaras N, Ugur M, Ozdemir S, Gurdal H, Purali N, Lacampagne A, Vassort G, Turan B (2005) Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes 54:3082–3088
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(1):234–246
Penpargkul S, Fein F, Sonnenblick EH, Scheuer J (1981) Depressed cardiac sarcoplasmic reticular function from diabetic rats. J Mol Cell Cardiol 13(3):303–309
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(4):H1398–H1408
Belke DD, Swanson EA, Dillmann WH (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53(12):3201–3208
Xu Y-J, Elimban V, Takeda S, Ren B, Takeda N, Dhalla NS (1996) Cardiac sarcoplasmic reticulum function and gene expression in chronic diabetes. Cardiovasc Pathol 1:89–96
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(3):947–959
Reuter H, Grönke S, Adam C, Ribati M, Brabender J, Zobel C, Frank KF, Wippermann J, Schwinger RH, Brixius K, Müller-Ehmsen J (2008) Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients. Mol Cell Biochem 308(1–2):141–149
Guner S, Arioglu E, Tay A, Tasdelen A, Aslamaci S, Bidasee KR, Dincer UD (2004) Diabetes decreases mRNA levels of calcium-release channels in human atrial appendage. Mol Cell Biochem 263(1–2):143–150
Bidasee KR, Nallani K, Henry B, Dincer UD, Besch HRJ (2003) Chronic diabetes alters function and expression of ryanodine receptor calcium-release channels in rat hearts. Mol Cell Biochem 249(1–2):113–123
Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278(45):44230–44237
Machackova J, Barta J, Dhalla NS (2005) Molecular defects in cardiac myofibrillar proteins due to thyroid hormone imbalance and diabetes. Can J Physiol Pharmacol 83(12):1071–1091
Kahaly GJ, Dillmann WH (2005) Thyroid hormone action in the heart. Endocr Rev 26(5):704–728
Kim HW, Ch YS, Lee HR, Park SY, Kim YH (2001) Diabetic alterations in cardiac sarcoplasmic reticulum Ca2+-ATPase and phospholamban protein expression. Life Sci 70(4):367–379
Ying J, Sharov V, Xu S, Jiang B, Gerrity R, Schöneich C, Cohen RA (2008) Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca(2+) ATPase in diabetic pig aorta. Free Radic Biol Med 45(6):756–762
Rastogi S, Sentex E, Elimban V, Dhalla NS, Netticadan T (2003) Elevated levels of protein phosphatase 1 and phosphatase 2A may contribute to cardiac dysfunction in diabetes. Biochim Biophys Acta 1638(3):273–277
Netticadan T, Temsah RM, Kent A, Elimban V, Dhalla NS (2001) Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart. Diabetes 50(9):2133–2138
Xiao B, Jiang MT, Zhao M, Yang D, Sutherland C, Lai FA, Walsh MP, Warltier DC, Cheng H, Chen SR (2005) Characterization of a novel PKA phosphorylation site, serine-2030, reveals no PKA hyperphosphorylation of the cardiac ryanodine receptor in canine heart failure. Circ Res 96(8):847–855
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(3):989–998
Tian C, Hong Shao C, Moore CJ, Kutty S, Walseth T, Desouza C, Bidasee KR (2011) Gain of function of cardiac ryanodine receptor in a rat model of type 1 diabetes. Cardiovasc Res 91(2):300–309
Munzel T, Gori T, Bruno RM, Taddei S (2010) Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 31:2741–2748
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
Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48(1):1–9
Uchida K (2000) Role of reactive aldehyde in cardiovascular diseases. Free Radic Biol Med 28(12):1685–1696
Vander Jagt DL (2008) Methylglyoxal, diabetes mellitus and diabetic complications. Drug Metabol Drug Interact 23(1–2):93–124
Ellis EM (2007) Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115(1):13–24
Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777(10):1249–1262
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
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
Thornalley PJ (1990) The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J 269:1–11
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
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
Barrera G, Pizzimenti S, Dianzani MU (2004) 4-hydroxynonenal and regulation of cell cycle: effects on the pRb/E2F pathway. Free Radic Biol Med 37(5):597–606
Dianzani MU (2003) 4-hydroxynonenal from pathology to physiology. Mol Aspects Med 24(4–5):263–272
Hovatta I, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM, Ellison JA, Schadt EE, Verma IM, Lockhart DJ, Barlow C (2005) Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438(7068):662–666
Distler MG, Plant LD, Sokoloff G, Hawk AJ, Aneas I, Wuenschell GE, Termini J, Meredith SC, Nobrega MA, Palmer AA (2012) Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal. J Clin Invest 122(6):2306–2315
Picklo MJ, Montine TJ, Amarnath V, Neely MD (2002) Carbonyl toxicology and Alzheimer’s disease. Toxicol Appl Pharmacol 184(3):187–197
Zarkovic K (2003) 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24(4–5):293–303
Bartsch H, Nair J (2004) Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis. Cancer Detect Prev 28(6):385–391
Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10(2):389–406
Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA (2008) Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem 283(32):21837–21841
Goudeau J, Aguilaniu H (2010) Carbonylated proteins are eliminated during reproduction in C. elegans. Aging Cell 9(6):991–1003
Shao CH, Tian C, Ouyang S, Moore CJ, Alomar F, Nemet I, D’Souza A, Nagai R, Kutty S, Rozanski GJ, Ramanadham S, Singh J, Bidasee KR (2012) Carbonylation induces heterogeneity in cardiac ryanodine receptor function in diabetes mellitus. Mol Pharmacol 82(3):383–399
Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, Haberkorn U, Brownlee M, Reeh PW, Nawroth PP (2012) Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18(6):926–933
Berner AK, Brouwers O, Pringle R, Klaassen I, Colhoun L, McVicar C, Brockbank S, Curry JW, Miyata T, Brownlee M, Schlingemann RO, Schalkwijk C, Stitt AW (2012) Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology. Diabetologia 55(3):845–854
Pedchenko VK, Chetyrkin SV, Chuang P, Ham AJ, Saleem MA, Mathieson PW, Hudson BG, Voziyan PA (2005) Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy. Diabetes 54(10):2952–2960
Moore CJ, Shao CH, Nagai R, Kutty S Singh J and Bidasee KR (2013) Absence of malondialdehyde and 4-hydroxynonenal adducts on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2) in diabetes. Mol Cell Biochem [Epub ahead of print]
Cheng Y-C, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108
de Lemos ET, Oliveira J, Pinheiro JP, Reis F (2012) Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev 22012:741545
Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR, HOPE and HOPE-TOO Trial Investigators (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293(11):1338–1347
Penckofer S, Schwertz D, Florczak K (2002) Oxidative stress and cardiovascular disease in type 2 diabetes: the role of antioxidants and pro-oxidants. J Cardiovasc Nurs 16(2):68–85
Rosenbaugh EG, Roat JW, Gao L, Yang RF, Manickam DS, Yin JX, Schultz HD, Bronich TK, Batrakova EV, Kabanov AV, Zucker IH, Zimmerman MC (2010) The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase. Biomaterials 31(19):5218–5226
Hartog JW, Willemsen S, van Veldhuisen DJ, Posma JL, van Wijk LM, Hummel YM, Hillege HL, Voors AA, BENEFICIAL investigators (2011) Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur J Heart Fail 13(8):899–908
Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, Wagle D, Shih D, Terlecky I, Bucala R, Cerami A, Egan J, Ulrich P (1996) An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 382(6588):275–278
Du J, Suzuki H, Nagase F, Akhand AA, Ma XY, Yokoyama T, Miyata T, Nakashima I (2001) Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. Free Radic Biol Med 31(4):469–478
Taha M, Lopaschuk GD (2007) Alterations in energy metabolism in cardiomyopathies. Ann Med 39:594–607
Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223
Iberg N, Flückiger R (1986) Nonenzymatic glycosylation of albumin in vivo. Identification of multiple glycosylated sites. J Biol Chem 261(29):13542–13545
Slatter DA, Bolton CH, Bailey AJ (2000) The importance of lipid-derived malondialdehyde in diabetes mellitus. Diabetologia 43:550–557
Marjani A (2010) Lipid peroxidation alterations in type 2 diabetic patients. Pak J Biol Sci 13:723–730
Piconi L, Quagliaro L, Ceriello A (2003) Oxidative stress in diabetes. Clin Chem Lab Med 41:1144–1149
Basu S (2004) Isoprostanes: novel bioactive products of lipid peroxidation. Free Radic Res 38:105–122
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
Li S, Li X, Li YL, Shao CH, Bidasee KR, Rozanski GJ (2008) Insulin regulation of glutathione and contractile Phenotype in diabetic rat ventricular myocytes. Am J Physiol 292(3):H1619–H1629
Acknowledgments
This work was supported in part by the grants from the Edna Ittner Research Foundation, American Diabetes Association (1-06-RA-11) and the National Institutes of Health (HL085061). 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. The authors apologize for relevant studies that have not been cited.
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Tian, C., Alomar, F., Moore, C.J. et al. Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart. Heart Fail Rev 19, 101–112 (2014). https://doi.org/10.1007/s10741-013-9384-9
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DOI: https://doi.org/10.1007/s10741-013-9384-9