Abstract
Endogenous histidyl dipeptides such as carnosine (β-alanine-l-histidine) form conjugates with lipid peroxidation products such as 4-hydroxy-trans-2-nonenal (HNE and acrolein), chelate metals, and protect against myocardial ischemic injury. Nevertheless, it is unclear whether these peptides protect against cardiac injury by directly reacting with lipid peroxidation products. Hence, to examine whether changes in the structure of carnosine could affect its aldehyde reactivity and metal chelating ability, we synthesized methylated analogs of carnosine, balenine (β-alanine-Nτ-methylhistidine) and dimethyl balenine (DMB), and measured their aldehyde reactivity and metal chelating properties. We found that methylation of Nτ residue of imidazole ring (balenine) or trimethylation of carnosine backbone at Nτ residue of imidazole ring and terminal amine group dimethyl balenine (DMB) abolishes the ability of these peptides to react with HNE. Incubation of balenine with acrolein resulted in the formation of single product (m/z 297), whereas DMB did not react with acrolein. In comparison with carnosine, balenine exhibited moderate acrolein quenching capacity. The Fe2+ chelating ability of balenine was higher than that of carnosine, whereas DMB lacked chelating capacity. Pretreatment of cardiac myocytes with carnosine increased the mean lifetime of myocytes superfused with HNE or acrolein compared with balenine or DMB. Collectively, these results suggest that carnosine protects cardiac myocytes against HNE and acrolein toxicity by directly reacting with these aldehydes. This reaction involves both the amino group of β-alanyl residue and the imidazole residue of l-histidine. Methylation of these sites prevents or abolishes the aldehyde reactivity of carnosine, alters its metal-chelating property, and diminishes its ability to prevent electrophilic injury.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abe H (2000) Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry (Mosc) 65(7):757–765
Aldini G, Carini M, Beretta G, Bradamante S, Facino RM (2002) Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? Biochem Biophys Res Commun 298(5):699–706
Baba SP, Hoetker JD, Merchant M, Klein JB, Cai J, Barski OA, Conklin DJ, Bhatnagar A (2013) Role of aldose reductase in the metabolism and detoxification of carnosine–acrolein conjugates. J Biol Chem 288(39):28163–28179. https://doi.org/10.1074/jbc.M113.504753
Baba SP, Zhang D, Singh M, Dassanayaka S, Xie Z, Jagatheesan G, Zhao J, Schmidtke VK, Brittian KR, Merchant ML, Conklin DJ, Jones SP, Bhatnagar A (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183–192. https://doi.org/10.1016/j.yjmcc.2018.04.002
Baran EJ (2000) Metal complexes of carnosine. Biochemistry (Mosc) 65(7):789–797
Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S (2013) Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 33(6):1162–1170. https://doi.org/10.1161/ATVBAHA.112.300572
Benderdour M, Charron G, DeBlois D, Comte B, Des Rosiers C (2003) Cardiac mitochondrial NADP + -isocitrate dehydrogenase is inactivated through 4-hydroxynonenal adduct formation: an event that precedes hypertrophy development. J Biol Chem 278(46):45154–45159. https://doi.org/10.1074/jbc.M306285200
Benderdour M, Charron G, Comte B, Ayoub R, Beaudry D, Foisy S, Deblois D, Des Rosiers C (2004) Decreased cardiac mitochondrial NADP + -isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development. Am J Physiol Heart Circ Physiol 287(5):H2122–2131. https://doi.org/10.1152/ajpheart.00378.2004
Benedetti A, Fulceri R, Ferrali M, Ciccoli L, Esterbauer H, Comporti M (1982) Detection of carbonyl functions in phospholipids of liver microsomes in CCl4- and BrCCl3-poisoned rats. Biochim Biophys Acta 712(3):628–638
Benedetti A, Comporti M, Fulceri R, Esterbauer H (1984) Cytotoxic aldehydes originating from the peroxidation of liver microsomal lipids. Identification of 4,5-dihydroxydecenal. Biochim Biophys Acta 792(2):172–181
Bhatnagar A (1995) Electrophysiological effects of 4-hydroxynonenal, an aldehydic product of lipid peroxidation, on isolated rat ventricular myocytes. Circ Res 76(2):293–304
Blancquaert L, Baba SP, Kwiatkowski S, Stautemas J, Stegen S, Barbaresi S, Chung W, Boakye AA, Hoetker JD, Bhatnagar A, Delanghe J, Vanheel B, Veiga-da-Cunha M, Derave W, Everaert I (2016) Carnosine and anserine homeostasis in skeletal muscle and heart is controlled by beta-alanine transamination. J Physiol. https://doi.org/10.1113/jp272050
Boldyrev AA, Aldini G, Derave W (2013) Physiology and pathophysiology of carnosine. Physiol Rev 93(4):1803–1845. https://doi.org/10.1152/physrev.00039.2012
Brown CE, Antholine WE, Froncisz W (1980) Multiple forms of the copper(II)-carnosine complex. J Chem Soc Dalton Trans 4:590–596
Brown CE, Vidrine DW, Julian RL, Froncisz W (1982) Copper (II) dimers in solution: evidence for motional averaging of coupling tensors without chemical dissociation. J Chem Soc Dalton Trans 12:2371–2377
Canabady-Rochelle LL, Harscoat-Schiavo C, Kessler V, Aymes A, Fournier F, Girardet JM (2015) Determination of reducing power and metal chelating ability of antioxidant peptides: revisited methods. Food Chem 183:129–135. https://doi.org/10.1016/j.foodchem.2015.02.147
Carini M, Aldini G, Beretta G, Arlandini E, Facino RM (2003) Acrolein-sequestering ability of endogenous dipeptides: characterization of carnosine and homocarnosine/acrolein adducts by electrospray ionization tandem mass spectrometry. J Mass Spectrom 38(9):996–1006. https://doi.org/10.1002/jms.517
Castro GJ, Bhatnagar A (1993) Effect of extracellular ions and modulators of calcium transport on survival of tert-butyl hydroperoxide exposed cardiac myocytes. Cardiovasc Res 27(10):1873–1881
Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321(5895):1493–1495. https://doi.org/10.1126/science.1158554
Conklin DJ, Guo Y, Jagatheesan G, Kilfoil PJ, Haberzettl P, Hill BG, Baba SP, Guo L, Wetzelberger K, Obal D, Rokosh DG, Prough RA, Prabhu SD, Velayutham M, Zweier JL, Hoetker JD, Riggs DW, Srivastava S, Bolli R, Bhatnagar A (2015) Genetic deficiency of glutathione S-Transferase P increases myocardial sensitivity to ischemia-reperfusion injury. Circ Res 117(5):437–449. https://doi.org/10.1161/CIRCRESAHA.114.305518
de Courten B, Jakubova M, de Courten MP, Kukurova IJ, Vallova S, Krumpolec P, Valkovic L, Kurdiova T, Garzon D, Barbaresi S, Teede HJ, Derave W, Krssak M, Aldini G, Ukropec J, Ukropcova B (2016) Effects of carnosine supplementation on glucose metabolism: pilot clinical trial. Obesity (Silver Spring) 24(5):1027–1034. https://doi.org/10.1002/oby.21434
Decker EA, Crum AD, Calvert JT (1992) Differences in the antioxidant mechanism of carnosine in the presence of copper and iron. J Agric Food Chem 40(5):756–759
Dobbie H, Kermack WO (1955) Complex-formation between polypeptides and metals. 2. The reaction between cupric ions and some dipeptides. Biochem J 59(2):246–257
Drozak J, Veiga-da-Cunha M, Vertommen D, Stroobant V, Van Schaftingen E (2010) Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). J Biol Chem 285(13):9346–9356. https://doi.org/10.1074/jbc.M109.095505
Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, Matsuhashi T, Katsumata Y, Zhang Y, Ito H, Nagahata Y, Marchitti S, Nishimaki K, Wolf AM, Nakanishi H, Hattori F, Vasiliou V, Adachi T, Ohsawa I, Taguchi R, Hirabayashi Y, Ohta S, Suematsu M, Ogawa S, Fukuda K (2009) Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circ Res 105(11):1118–1127. https://doi.org/10.1161/CIRCRESAHA.109.206607
Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128
Fawaz MV, Topper ME, Firestine SM (2011) The ATP-grasp enzymes. Bioorg Chem 39(5–6):185–191. https://doi.org/10.1016/j.bioorg.2011.08.004
Freeman HC, Szymanski JT (1967) Crystallographic studies of metal-peptide complexes. V. (Beta-alanyl-l-histidinato)copper(II)dihydrate. Acta Crystallogr 22(3):406–417
Giordano FJ (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 115(3):500–508. https://doi.org/10.1172/JCI24408
Gomes KM, Campos JC, Bechara LR, Queliconi B, Lima VM, Disatnik MH, Magno P, Chen CH, Brum PC, Kowaltowski AJ, Mochly-Rosen D, Ferreira JC (2014) Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling. Cardiovasc Res 103(4):498–508. https://doi.org/10.1093/cvr/cvu125
Halliwell BGJ (2015) Free radical in biology and medicine. Oxford University Press, Oxford
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334(18):1145–1149. https://doi.org/10.1056/NEJM199605023341801
Hipkiss AR (2009) Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res 57:87–154. https://doi.org/10.1016/S1043-4526(09)57003-9
Ishikawa T, Esterbauer H, Sies H (1986) Role of cardiac glutathione transferase and of the glutathione S-conjugate export system in biotransformation of 4-hydroxynonenal in the heart. J Biol Chem 261(4):1576–1581
Ismahil MA, Hamid T, Haberzettl P, Gu Y, Chandrasekar B, Srivastava S, Bhatnagar A, Prabhu SD (2011) Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 301(5):H2050–2060. https://doi.org/10.1152/ajpheart.00120.2011
Kato Y, Iwase M, Ichihara S, Kanazawa H, Hashimoto K, Noda A, Nagata K, Koike Y, Yokota M (2010) Beneficial effects of growth hormone-releasing peptide on myocardial oxidative stress and left ventricular dysfunction in dilated cardiomyopathic hamsters. Circ J 74(1):163–170
Keith RJ, Haberzettl P, Vladykovskaya E, Hill BG, Kaiserova K, Srivastava S, Barski O, Bhatnagar A (2009) Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts. Chem Biol Interact 178(1–3):242–249. https://doi.org/10.1016/j.cbi.2008.10.055
Kurhanewicz N, McIntosh-Kastrinsky R, Tong H, Ledbetter A, Walsh L, Farraj A, Hazari M (2017) TRPA1 mediates changes in heart rate variability and cardiac mechanical function in mice exposed to acrolein. Toxicol Appl Pharmacol 324:51–60. https://doi.org/10.1016/j.taap.2016.10.008
Lenz GR, Martell AE (1964) Metal complexes of carnosine. Biochemistry 3:750–753
Liu YH, Carretero OA, Cingolani OH, Liao TD, Sun Y, Xu J, Li LY, Pagano PJ, Yang JJ, Yang XP (2005) Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289(6):H2616–2623. https://doi.org/10.1152/ajpheart.00546.2005
Moreau R, Heath SH, Doneanu CE, Lindsay JG, Hagen TM (2003) Age-related increase in 4-hydroxynonenal adduction to rat heart alpha-ketoglutarate dehydrogenase does not cause loss of its catalytic activity. Antioxid Redox Signal 5(5):517–527. https://doi.org/10.1089/152308603770310167
Niki E (2009) Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med 47(5):469–484. https://doi.org/10.1016/j.freeradbiomed.2009.05.032
Okuma HAAE (1991) Effect of Temperature on the buffering capacities of histidine-related compounds and fish skeletal muscle. Nippon Suisan Gakkaishi 57(11):2101–2107
Orioli M, Vistoli G, Regazzoni L, Pedretti A, Lapolla A, Rossoni G, Canevotti R, Gamberoni L, Previtali M, Carini M, Aldini G (2011) Design, synthesis, ADME properties, and pharmacological activities of beta-alanyl-d-histidine (d-carnosine) prodrugs with improved bioavailability. Chem Med Chem 6(7):1269–1282. https://doi.org/10.1002/cmdc.201100042
Porter NA, Caldwell SE, Mills KA (1995) Mechanisms of free radical oxidation of unsaturated lipids. Lipids 30(4):277–290
Qin F, Simeone M, Patel R (2007) Inhibition of NADPH oxidase reduces myocardial oxidative stress and apoptosis and improves cardiac function in heart failure after myocardial infarction. Free Radic Biol Med 43(2):271–281. https://doi.org/10.1016/j.freeradbiomed.2007.04.021
Sansbury BE, DeMartino AM, Xie Z, Brooks AC, Brainard RE, Watson LJ, DeFilippis AP, Cummins TD, Harbeson MA, Brittian KR, Prabhu SD, Bhatnagar A, Jones SP, Hill BG (2014) Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. Circ Heart Fail 7(4):634–642. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001151
Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS (2002) Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 34(4):379–388. https://doi.org/10.1006/jmcc.2002.1526
Shinmura K, Bolli R, Liu SQ, Tang XL, Kodani E, Xuan YT, Srivastava S, Bhatnagar A (2002) Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circ Res 91(3):240–246
Srivastava S, Harter TM, Chandra A, Bhatnagar A, Srivastava SK, Petrash JM (1998) Kinetic studies of FR-1, a growth factor-inducible aldo-keto reductase. Biochemistry 37(37):12909–12917. https://doi.org/10.1021/bi9804333
Srivastava S, Watowich SJ, Petrash JM, Srivastava SK, Bhatnagar A (1999) Structural and kinetic determinants of aldehyde reduction by aldose reductase. Biochemistry 38(1):42–54. https://doi.org/10.1021/bi981794l
Srivastava S, Chandrasekar B, Gu Y, Luo J, Hamid T, Hill BG, Prabhu SD (2007) Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res 74(3):445–455. https://doi.org/10.1016/j.cardiores.2007.02.016
Sun A, Cheng Y, Zhang Y, Zhang Q, Wang S, Tian S, Zou Y, Hu K, Ren J, Ge J (2014a) Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy. J Mol Cell Cardiol 71:92–104. https://doi.org/10.1016/j.yjmcc.2014.01.002
Sun A, Zou Y, Wang P, Xu D, Gong H, Wang S, Qin Y, Zhang P, Chen Y, Harada M, Isse T, Kawamoto T, Fan H, Yang P, Akazawa H, Nagai T, Takano H, Ping P, Komuro I, Ge J (2014b) Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice. J Am Heart Assoc 3(5):e000779. https://doi.org/10.1161/JAHA.113.000779
van der Kraaij AM, de Jonge HR, Esterbauer H, de Vente J, Steinbusch HW, Koster JF (1990) Cumene hydroperoxide, an agent inducing lipid peroxidation, and 4-hydroxy-2,3-nonenal, a peroxidation product, cause coronary vasodilatation in perfused rat hearts by a cyclic nucleotide independent mechanism. Cardiovasc Res 24(2):144–150
Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342(3):154–160. https://doi.org/10.1056/nejm200001203420302
Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y (2007) Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res 100(7):1089–1098. https://doi.org/10.1161/01.RES.0000264081.78659.45
Zhang P, Hou M, Li Y, Xu X, Barsoum M, Chen Y, Bache RJ (2009) NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart. Am J Physiol Heart Circ Physiol 296(3):H840–846. https://doi.org/10.1152/ajpheart.00519.2008
Acknowledgements
We would like to thank Bioanalytical Core of the Diabetes and Obesity Center for biochemical analysis.
Funding
This work was supported by grants from the National Institutes of Health, R01HL122581-01 (SPB), R01HL55477 and GM103492 (AB).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
All authors declare that no competing financial interest exists.
Ethical approval
All treatments and protocols were approved by the University of Louisville, Institutional Animal Care and Use Committee. The ethical approval number is 15387.
Additional information
Handling Editor: W. Derave.
Rights and permissions
About this article
Cite this article
Zhao, J., Posa, D.K., Kumar, V. et al. Carnosine protects cardiac myocytes against lipid peroxidation products. Amino Acids 51, 123–138 (2019). https://doi.org/10.1007/s00726-018-2676-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-018-2676-6