Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: Role of mitochondrial dysfunction

Neetu Sud, Sandra M. Wells, Shruti Sharma, Dean A. Wiseman, Jason Wilham, Stephen M. Black

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Increased asymmetric dimethylarginine (ADMA) levels have been implicated in the pathogenesis of a number of conditions affecting the cardiovascular system. However, the mechanism(s) by which ADMA exerts its effect has not been adequately elucidated. Thus the purpose of this study was to determine the effect of increased ADMA on nitric oxide (NO) signaling and to begin to elucidate the mechanism by which ADMA acts. Our initial data demonstrated that ADMA increased NO synthase (NOS) uncoupling in both recombinant human endothelial NO synthase (eNOS) and pulmonary arterial endothelial cells (PAEC). Furthermore, we found that this endothelial NOS (eNOS) uncoupling increased 3-nitrotyrosine levels preferentially in the mitochondria of PAEC due to a redistribution of eNOS from the plasma membrane to the mitochondria. This increase in nitration in the mitochondria was found to induce mitochondrial dysfunction as determined by increased mitochondrial-derived reactive oxygen species and decreased generation of ATP. Finally, we found that the decrease in ATP resulted in a reduction in the chaperone activity of HSP90 resulting in a decrease in its interaction with eNOS. In conclusion increased levels of ADMA causes mitochondrial dysfunction and a loss of heat shock protein-90 chaperone activity secondary to an uncoupling of eNOS. Mitochondrial dysfunction may be an understudied component of the endothelial dysfunction associated with various cardiovascular disease states.

Original languageEnglish (US)
Pages (from-to)C1407-C1418
JournalAmerican Journal of Physiology - Cell Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 1 2008

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Keywords

  • Mitochondria
  • Oxidative stress
  • Peroxynitrite
  • Protein-protein interactions

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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