Regulation of SERCA Via Oxidative Modifications: Implications for the Pathophysiology of Diastolic Dysfunction in the Aging Heart

  • Fuzhong Qin
  • Richard A. Cohen
  • Wilson S. ColucciEmail author


Aging is associated with left ventricular hypertrophy and diastolic dysfunction. The characteristic cellular changes in aging myocardium include myocyte hypertrophy, interstitial fibrosis, and impaired myocyte relaxation. An extensive body of work suggests that calcium dysregulation contributes to impaired myocyte function in aging. Sarcoplasmic reticular (SR) calcium ATPase (SERCA) plays a particularly important role in maintaining intracellular calcium homeostasis. In cardiac myocytes in vitro, we have shown that oxidants (e.g., nitroxyl or peroxynitrite) in low, “physiologic” levels cause reversible S-glutathiolation of SERCA at cysteine 674 (C674) leading to activation. In contrast, higher levels of oxidants (e.g., H2O2 or peroxynitrite that may be associated with pathologic conditions lead to irreversible oxidation of SERCA at one or more sites, including sulfonation at C674. Irreversible oxidation of C674 may inhibit basal enzyme activity and further prevent activation via S-glutathiolation. Studies in aging myocardium have further demonstrated irreversible oxidation of SERCA cysteines and nitration of tyrosines. We have observed that myocardial levels of 3-nitrotyrosine and 4-HNE indicative of oxidative stress and sulfonation of SERCA at C674 are markedly increased in aging hearts and that these increases are prevented in transgenic mice with catalase overexpression. Furthermore, catalase overexpression prevents decreased SERCA activity and impaired diastolic function in myocytes from aging hearts. These studies suggest that reactive oxygen species such as H2O2 contribute to impaired diastolic function in cardiac aging, at least in part via oxidative modification of SERCA, and in particular, via sulfonation at C674. Strategies to target oxidant sources, decrease oxidant levels, and/or protect target proteins such as SERCA from irreversible oxidation may be of value in the amelioration of diastolic function in cardiac aging and perhaps other conditions associated with diastolic dysfunction.


Diastolic Dysfunction Cardiac Myocytes Reactive Oxidative Species Irreversible Oxidation Aging Heart 
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  1. 1.
    Chen MA. Heart failure with preserved ejection fraction in older adults. Am J Med. 2009;122(8):713–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Aronow WS. Left ventricular diastolic heart failure with normal left ventricular systolic function in older persons. J Lab Clin Med. 2001;137(5):316–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009;119(21):2789–97.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Dai DF, Rabinovitch PS. Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. Trends Cardiovasc Med. 2009;19(7):213–20.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003;107(2):346–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Oxenham H, Sharpe N. Cardiovascular aging and heart failure. Eur J Heart Fail. 2003;5(4):427–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Chen W, Frangogiannis NG. The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev. 2010;15(5):415–22.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Dai DF, Linford NJ, Santana LF, Treuting P, Ladiges W, Rabinovitch PS. Mice overexpressing mitochondrial-targeted catalase are protected against cardiac aging. Eur Heart J. 2006;27:875–6.CrossRefGoogle Scholar
  9. 9.
    Groban L. Diastolic dysfunction in the older heart. J Cardiothorac Vasc Anesth. 2005;19(2):228–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Boyle AJ, Shih H, Hwang J, et al. Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. Exp Gerontol. 2011;46(7):549–59.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E. Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res. 2012;110(8):1125–38.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107(3):490–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Kitzman DW. Diastolic heart failure in the elderly. Heart Fail Rev. 2002;7(1):17–27.PubMedCrossRefGoogle Scholar
  14. 14.
    Bernhard D, Laufer G. The aging cardiomyocyte: a mini-review. Gerontology. 2008;54(1):24–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Janczewski AM, Lakatta EG. Modulation of sarcoplasmic reticulum Ca(2+) cycling in systolic and diastolic heart failure associated with aging. Heart Fail Rev. 2010;15(5):431–45.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Davies CH, Davia K, Bennett JG, Pepper JR, Poole-Wilson PA, Harding SE. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation. 1995;92(9):2540–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Houck WV, Pan LC, Kribbs SB, et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100(19):2003–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Kinugawa S, Tsutsui H, Ide T, et al. Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes. Cardiovasc Res. 1999;43(1):157–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Zarain-Herzberg A. Regulation of the sarcoplasmic reticulum Ca2 + −ATPase expression in the hypertrophic and failing heart. Can J Physiol Pharmacol. 2006;84(5):509–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Lim C, Liao R, Varma N, Apstein CS. Impaired myocardial relaxation in the senescent mouse heart correlates with age-related alterations in calcium handling proteins. Biophys J. 1999;76(1):A309.Google Scholar
  21. 21.
    Ren J, Li Q, Wu S, Li SY, Babcock SA. Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Ageing Dev. 2007;128(3):276–85.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Lim CC, Apstein CS, Colucci WS, Liao RL. Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte. J Mol Cell Cardiol. 2000;32(11):2075–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Lancel S, Qin FZ, Lennon SL, et al. Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in G alpha q-overexpressing mice. Circ Res. 2010; 107(2):228–32.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Adachi T, Weisbrod RM, Pimentel DR, et al. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat Med. 2004;10(11):1200–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Li SY, Du M, Dolence EK, et al. Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell. 2005;4(2):57–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Rueckschloss U, Villmow M, Klockner U. NADPH oxidase-derived superoxide impairs calcium transients and contraction in aged murine ventricular myocytes. Exp Gerontol. 2010;45(10):788–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Wang MY, Zhang J, Walker SJ, Dworakowski R, Lakatta EG, Shah AM. Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol. 2010;48(4):765–72.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Wu S, Li Q, Du M, Li SY, Ren J. Cardiac-specific overexpression of catalase prolongs lifespan and attenuates ageing-induced cardiomyocyte contractile dysfunction and protein damage. Clin Exp Pharmacol Physiol. 2007;34(1–2):81–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Bishop JE, Squier TC, Bigelow DJ, Inesi G. (Iodoacetamido)fluorescein labels a pair of proximal cysteines on the Ca2 + −ATPase of sarcoplasmic reticulum. Biochemistry. 1988;27(14):5233–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Ying J, Tong X, Pimentel DR, et al. Cysteine-674 of the sarco/endoplasmic reticulum calcium ATPase is required for the inhibition of cell migration by nitric oxide. Arterioscler Thromb Vasc Biol. 2007;27(4):783–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Tong X, Hou X, Jourd'heuil D, Weisbrod RM, Cohen RA. Upregulation of Nox4 by TGF{beta}1 oxidizes SERCA and inhibits NO in arterial smooth muscle of the prediabetic Zucker rat. Circ Res. 2010;107(8):975–83.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lancel S, Zhang J, Evangelista A, et al. Nitroxyl activates SERCA in cardiac myocytes via glutathiolation of cysteine 674. Circ Res. 2009;104(6):720–3.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Evangelista AM, Thompson MD, Weisbrod RM, et al. Redox regulation of SERCA2 is required for vascular endothelial growth factor-induced signaling and endothelial cell migration. Antioxid Redox Signal. 2012;17(8):1099–108.PubMedCrossRefGoogle Scholar
  34. 34.
    Ying J, Sharov V, Xu S, et al. Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca(2+) ATPase in diabetic pig aorta. Free Radic Biol Med. 2008;45(6):756–62.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Tong X, Ying J, Pimentel DR, Trucillo M, Adachi T, Cohen RA. High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration. J Mol Cell Cardiol. 2008;44(2):361–9.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Adachi T, Matsui R, Weisbrod RM, Najibi S, Cohen RA. Reduced sarco/endoplasmic reticulum Ca(2+) uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta. Circulation. 2001;104(9):1040–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Adachi T, Matsui R, Xu S, et al. Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca(2+)-ATPase function and lowers tyrosine nitration in hypercholesterolemia and improves nitric oxide-induced relaxation. Circ Res. 2002;90(10):1114–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Kuster GM, Lancel S, Zhang JM, et al. Redox-mediated reciprocal regulation of SERCA and Na(+)-Ca(2+) exchanger contributes to sarcoplasmic reticulum Ca(2+) depletion in cardiac myocytes. Free Radic Biol Med. 2010;48(9):1182–7.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Qin F, Biolo A, Siwik DA, et al. Cardiac-specific overexpression of catalase prevents progressive left ventricular remodeling and failure in gq-overexpressing transgenic mice. Circulation. 2006;114(18):155.Google Scholar
  40. 40.
    Qin F, Luptak I, Siwik DA, Kang L, Cohen RA, Colucci WS. Myocyte-specific catalase overexpression prevents age-related left ventricular diastolic dysfunction: association with reduction of oxidation of SERCA at cysteine 674 Abstract. Circulation. 2011;124:A9575.Google Scholar
  41. 41.
    Schmidt U. del MF, Miyamoto MI et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation. 2000;101(7):790–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhu X, Altschafl BA, Hajjar RJ, Valdivia HH, Schmidt U. Altered Ca2+ sparks and gating properties of ryanodine receptors in aging cardiomyocytes. Cell Calcium. 2005;37(6):583–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Isenberg G, Borschke B, Rueckschloss U. Ca2+ transients of cardiomyocytes from senescent mice peak late and decay slowly. Cell Calcium. 2003;34(3):271–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Slack JP, Grupp IL, Dash R, et al. The enhanced contractility of the phospholamban-deficient mouse heart persists with aging. J Mol Cell Cardiol. 2001;33(5):1031–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Thomas MM, Vigna C, Betik AC, Tupling AR, Hepple RT. Cardiac calcium pump inactivation and nitrosylation in senescent rat myocardium are not attenuated by long-term treadmill training. Exp Gerontol. 2011;46(10):803–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Periasamy M, Bhupathy P, Babu GJ. Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc Res. 2008;77(2):265–73.PubMedCrossRefGoogle Scholar
  47. 47.
    Sharov VS, Dremina ES, Galeva NA, Williams TD, Schoneich C. Quantitative mapping of oxidation-sensitive cysteine residues in SERCA in vivo and in vitro by HPLC-electrospray-tandem MS: selective protein oxidation during biological aging. Biochem J. 2006;394(Pt 3):605–15.PubMedGoogle Scholar
  48. 48.
    Knyushko TV, Sharov VS, Williams TD, Schoneich C, Bigelow DJ. 3-Nitrotyrosine modification of SERCA2a in the aging heart: a distinct signature of the cellular redox environment. Biochemistry. 2005;44(39):13071–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Xu SQ, Ying J, Jiang BB, et al. Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol. 2006;290(6):H2220–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Fuzhong Qin
    • 1
  • Richard A. Cohen
    • 2
  • Wilson S. Colucci
    • 3
    Email author
  1. 1.Cardiovascular Medicine SectionBoston University Medical CenterBostonUSA
  2. 2.Department of MedicineBoston University School of MedicineBostonUSA
  3. 3.Boston University Medical CenterBostonUSA

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