Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma

Nasrin Mesaeli, Paramjit S. Tappia, Shingo Suzuki, Naranjan S. Dhalla, Vincenzo Panagia

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) is the substrate for phosphoinositide-phospholipase C (PLC) and is required for the function of several cardiac cell plasma membrane (sarcolemma, SL) proteins. PtdIns 4,5-P2 is synthesized in the SL membrane by coordinated and successive actions of PtdIns 4-kinase and PtdIns 4-phosphate 5-kinase. These kinases and the generation of PtdIns 4,5-P2 may be a factor in the cardiac dysfunction during pathophysiological conditions of oxidative stress. Therefore, we examined the effects of different reactive oxygen species (ROS) on the kinases' activities and subsequent generation of PtdIns 4,5-P2. Exposure to the xanthine-xanthine oxidase-ROS generating system significantly reduced both SL kinase activities. Superoxide dismutase did not prevent this inhibition; however, catalase significantly prevented the xanthine-xanthine oxidase induced inhibition. Treatment of SL with hydrogen peroxide (H2O2) resulted in inhibition of both the kinases, which was prevented by catalase and dithiothreitol (DTT). Hypochlorous acid also inhibited both the kinases, which was prevented by DTT. Deferoxamine (an iron chelator) and mannitol (an (·)OH scavenger) did not modify the H2O2-induced depression of the kinases, eliminating any role of (·)OH. Furthermore, the IC50 of H2O2 on PtdIns 4-kinase and PtdIns 4-P 5-kinase was 27 and 81 μM, respectively. In addition, inclusion of reduced glutathione in the assay of the kinases in the absence of H2O2 did not affect the activities of the kinases; however, oxidized glutathione induced a significant depression. Also, a significant decline of the PtdIns 4-kinase and PtdIns 4-P 5-kinase activities due to changing of the redox ratio was observed. Thiol modifiers (N-ethylmaleimide, methyl methanethiosulfonate, or p-chloromercuriphenylsulfonic acid) were detected to depress the kinases' activities, which were substantially prevented by DTT. The results suggest that functionally critical thiol groups may be associated with PtdIns 4-kinase and PtdIns 4-P 5-kinase and that changes of their redox state by ROS can impair their activities, which may be an important factor in the oxidant-induced cardiac dysfunction. (C) 2000 Academe Press.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume382
Issue number1
DOIs
Publication statusPublished - 1 Oct 2000
Externally publishedYes

Fingerprint

Sarcolemma
Phosphatidylinositols
Oxidants
Phosphotransferases
Phosphatidylinositol 4,5-Diphosphate
1-Phosphatidylinositol 4-Kinase
Dithiothreitol
Reactive Oxygen Species
Xanthine
Xanthine Oxidase
Sulfhydryl Compounds
Cell membranes
Catalase
Oxidation-Reduction
Cell Membrane
Phosphoinositide Phospholipase C
Hypochlorous Acid
Ethylmaleimide
Deferoxamine
Glutathione Disulfide

Keywords

  • Oxidants
  • Phosphatidylinositol 4,5-bisphosphate
  • Phosphatidylinositol 4-kinase
  • Phosphatidylinositol 4-phosphate 5-kinase
  • Rat heart sarcolemma
  • Sulfhydryl groups

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma. / Mesaeli, Nasrin; Tappia, Paramjit S.; Suzuki, Shingo; Dhalla, Naranjan S.; Panagia, Vincenzo.

In: Archives of Biochemistry and Biophysics, Vol. 382, No. 1, 01.10.2000, p. 48-56.

Research output: Contribution to journalArticle

Mesaeli, Nasrin ; Tappia, Paramjit S. ; Suzuki, Shingo ; Dhalla, Naranjan S. ; Panagia, Vincenzo. / Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma. In: Archives of Biochemistry and Biophysics. 2000 ; Vol. 382, No. 1. pp. 48-56.
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