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

  • Fuzhong Qin
  • Richard A. Cohen
  • Wilson S. Colucci
Chapter

Abstract

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.

Keywords

Diastolic Dysfunction Cardiac Myocytes Reactive Oxidative Species Irreversible Oxidation Aging Heart 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Fuzhong Qin
    • 1
  • Richard A. Cohen
    • 2
  • Wilson S. Colucci
    • 3
  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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