Prolonged oxidative stress inverts the cardiac force-frequency relation: Role of altered calcium handling and myofilament calcium responsiveness

Academic Article

Abstract

  • The normally positive force- and Ca -frequency responses (FFR and CaFR) are inverted in heart failure (HF); whether oxidative stress contributes to these abnormalities is unknown. We evaluated the impact of acute and prolonged oxidative stress on contraction and Ca handling in adult rat cardiomyocytes. Acute (30:min) exposure to H O (100 μM) induced a twofold increase (P < 0.025) in intracellular oxyradicals together with contractile depression despite preservation of the Ca transient and the FFR and CaFR to 3:Hz, indicating reduced myofilament Ca responsiveness. In contrast, prolonged (24:h) exposure to the copper-zinc superoxide dismutase inhibitor diethyldithiocarbamic acid (DDC, 1 μM) similarly augmented oxyradicals but also increased cell size, and contraction and Ca transient duration (P < 0.025). DDC-treated myocytes displayed inverted FFRs and attenuated (though still positive) CaFRs as compared to control, indicating reduced myofilament Ca responsiveness coupled with altered Ca handling. Protein levels of the Na -Ca exchanger (NCX), sarcoplasmic reticular (SR) Ca ATPase (SERCA2), and serine-16 phosphorylated phospholamban (pSer16-PLB) were increased (P < 0.025), whereas dihydropyridine receptor abundance was decreased. Total PLB and ryanodine receptor protein expression were unchanged. Caffeine-induced Ca release showed increased NCX activity (P < 0.025) without changes in total releasable SR Ca , suggesting compensatory changes in SERCA2 and pSer16-PLB to maintain SR Ca load. The superoxide scavenger Tiron attenuated these effects. Thus, acute oxyradical exposure rapidly depresses myofibrillar Ca responsiveness. Prolonged oxidative stress further induces alterations in Ca handling that combined with extant reductions in myofibrillar responsiveness invert the FFR. With regard to Ca handling, reduced transsarcolemmal Ca flux rather than reduced SR Ca uptake was the primary determinant of a negative FFR. Analogous changes may be operative in HF, a state characterized by both oxidative stress and Ca dysregulation. © 2005 Elsevier Ltd. All rights reserved. 2+ 2+ 2+ 2+ 2+ 2+ 2+ + 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2 2
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Luo J; Xuan YT; Gu Y; Prabhu SD
  • Start Page

  • 64
  • End Page

  • 75
  • Volume

  • 40
  • Issue

  • 1