Protein kinase A-mediated phosphorylation modulates cytochrome c oxidase function and augments hypoxia and myocardial ischemia-related injury

Subbuswamy K. Prabu, Hindupur K. Anandatheerthavarada, Haider Raza, Satish Srinivasan, Joseph F. Spear, Narayan G. Avadhani

Research output: Contribution to journalArticlepeer-review

164 Citations (Scopus)

Abstract

We have investigated the effects of hypoxia and myocardial ischemia/ reperfusion on the structure and function of cytochrome c oxidase (CcO). Hypoxia (0.1% O2 for 10 h) and cAMP-mediated inhibition of CcO activity were accompanied by hyperphosphorylation of subunits I, IVi1, and Vb and markedly increased reactive O2 species production by the enzyme complex in an in vitro system that uses reduced cytochrome c as an electron donor. Both subunit phosphorylation and enzyme activity were effectively reversed by 50 nM H89 or 50 nM myristoylated peptide inhibitor (MPI), specific inhibitors of protein kinase A, but not by inhibitors of protein kinase C. In rabbit hearts subjected to global and focal ischemia, CcO activity was inhibited in a time-dependent manner and was accompanied by hyperphosphorylation as in hypoxia. Additionally, CcO activity and subunit phosphorylation in the ischemic heart were nearly completely reversed by H89 or MPI added to the perfusion medium. Hyperphosphorylation of subunits I, IVi1, and Vb was accompanied by reduced subunit contents of the immunoprecipitated CcO complex. Most interestingly, both H89 and MPI added to the perfusion medium dramatically reduced the ischemia/reperfusion injury to the myocardial tissue. Our results pointed to an exciting possibility of using CcO activity modulators for controlling myocardial injury associated with ischemia and oxidative stress conditions.

Original languageEnglish
Pages (from-to)2061-2070
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number4
DOIs
Publication statusPublished - Jan 27 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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