Effects of peroxynitrite on isolated cardiac trabeculae: Selective impact on myofibrillar energetic controllers

Michael J. Mihm, Fushun Yu, Peter J. Reiser, John Anthony Bauer

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Formation of peroxynitrite and cardiac protein nitration have been implicated in multiple cardiac disease states, but their contributions to disease initiation remain undefined. We have previously observed nitration of myofibrillar regions of cardiac myocytes in several experimental and clinical settings of cardiac myocyte dysfunction and postulated that oxidative insult to key components of the contractile apparatus may be initiating events. Here we tested the hypothesis that peroxynitrite alters myofibrillar contractile function, and investigated a mechanistic role for nitration in this process. Isolated rat ventricular trabeculae were exposed to physiologically relevant concentrations of peroxynitrite and ATP-dependent contractile responses were measured. Maximal trabecular force generation was significantly impaired following 300 nM peroxynitrite exposures. Several myofibrillar proteins demonstrated increased tyrosine nitration, the most significant increases occurred in the myosin heavy chain and the myofibrillar isoform of creatine kinase. Additional functional experiments were conducted using phosphocreatine (high energy phosphate substrate for myofibrillar creatine kinase) as the primary energy substrate. Myofibrillar creatine kinase-dependent force generation was impaired at peroxynitrite concentrations as low as 50 nM, suggesting potent inactivation of the enzyme. Extent of tyrosine nitration of myofibrillar creatine kinase was negatively correlated to myofibrillar creatine kinase-dependent force generation. These data demonstrate that the cardiac contractile apparatus is highly sensitive to peroxynitrite, and that MM-CK may be a uniquely vulnerable target.

Original languageEnglish
Pages (from-to)587-596
Number of pages10
Issue number6
StatePublished - Jun 1 2003

Bibliographical note

Funding Information:
This work was supported in part by grants from the National Institutes of Health (HL59791, DK55053, HL63067) and an award from the American Heart Association, Ohio Valley Affiliate.


  • Creatine kinase
  • Energetics
  • Peroxynitrite
  • Proteomics

ASJC Scopus subject areas

  • Biochemistry


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