cAMP-independent activation of protein kinase A by the peroxynitrite generator SIN-1 elicits positive inotropic effects in cardiomyocytes

Mark Kohr, Christopher J. Traynham, Steve R. Roof, Jonathan P. Davis, Mark T. Ziolo

Research output: Contribution to journalArticle

Abstract

The phosphatase vs. kinase equilibrium plays a critical role in the regulation of myocardial contractility. Previous studies have demonstrated that peroxynitrite exerts a biphasic effect on cardiomyocyte contraction, such that high peroxynitrite reduced β-adrenergic-stimulated myocyte contraction by inducing the dephosphorylation of phospholamban (PLB) via phosphatase activation. Conversely, low peroxynitrite increased basal and β-adrenergic-stimulated contraction also through a PLB-dependent mechanism. However, previous studies have not elucidated the mechanism underlying the positive effects of low peroxynitrite on myocyte contraction. In the current study, we examined the phosphatase vs. kinase equilibrium as a potential mechanism underlying the positive effects of peroxynitrite. SIN-1 (peroxynitrite donor, 10 μmol/L) increased myocyte Ca2+ transient and shortening amplitude, accelerated myocyte relaxation, and enhanced PLB phosphorylation. Specific inhibition of PP1/PP2a with okadaic acid failed to inhibit this positive effect. However, inhibition of PKA with KT5720 completely abolished the effects of SIN-1 on myocyte contraction. Additionally, SIN-1 induced a significant increase in PKA activity in cardiac homogenates, which was inhibited with FeTPPS (peroxynitrite decomposition catalyst). Surprisingly, SIN-1 also increased activity in purified preparations (i.e., in the absence of cAMP) of PKA. Therefore, our data suggest that peroxynitrite directly activates PKA (independent from cAMP), resulting in the enhancement of myocyte contraction and relaxation through the phosphorylation of PLB.

Original languageEnglish (US)
Pages (from-to)645-648
Number of pages4
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
Muscle Cells
Phosphoric Monoester Hydrolases
Adrenergic Agents
Phosphotransferases
Phosphorylation
Okadaic Acid

Keywords

  • NOS1
  • Phosphatase
  • Phospholamban
  • PKA

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

cAMP-independent activation of protein kinase A by the peroxynitrite generator SIN-1 elicits positive inotropic effects in cardiomyocytes. / Kohr, Mark; Traynham, Christopher J.; Roof, Steve R.; Davis, Jonathan P.; Ziolo, Mark T.

In: Journal of Molecular and Cellular Cardiology, Vol. 48, No. 4, 04.2010, p. 645-648.

Research output: Contribution to journalArticle

Kohr, Mark ; Traynham, Christopher J. ; Roof, Steve R. ; Davis, Jonathan P. ; Ziolo, Mark T. / cAMP-independent activation of protein kinase A by the peroxynitrite generator SIN-1 elicits positive inotropic effects in cardiomyocytes. In: Journal of Molecular and Cellular Cardiology. 2010 ; Vol. 48, No. 4. pp. 645-648.
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