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P25 Heart failure increases myocardial s-nitrosylation
  1. EJ Radcliffe1,
  2. J Sun2,
  3. A Aponte2,
  4. DW Eisner1,
  5. E Murphy2,
  6. AW Trafford1
  1. 1The University of Manchester, UK
  2. 2National Heart, Lung and Blood Institute, NIH, USA


The availability of ATP is a limiting factor to cardiac contraction. ATP is predominantly produced by mitochondria via oxidative phosphorylation. Nitric oxide acts as a competitive inhibitor of complex IV and following ischemia, S-nitrosylation has been shown to inhibit complex I activity. Given the established role for nitric oxide in the regulation of oxidative phosphorylation, it is the aim of this study to determine if nitric oxide signalling plays a regulatory role in ATP production in the failing heart.

An ovine tachypaced model of heart failure has been used. 4–6 weeks tachypacing resulted in an increase in left ventricular diameter (3.10±0.06 cm to 4.04±0.13 cm, p<0.01, n=5) and a reduction in left ventricular contractility (0.47±0.01 to 0.20±0.03, p<0.01, n=5). Following sacrifice, left ventricular, posterior free wall samples were snap frozen and enriched for S-nitrosylation using resin assisted capture. Samples were quantified using mass spectrometry. 232±18 discrete proteins were identified as nitrosylated in the control myocardium. This increased to 314±28.3 in the heart failure (p=0.02, n=6). Additionally, 79% of nitrosylated proteins also showed an increase in S-nitrosylation abundance. Several specific sites of S-nitrosylation in heart failure were identified within the electron transport chain; the subunits NDUFS1, SDHA and UQCRH all had a greater than 1 fold increase in nitrosylation in the disease state.

This study is the first to demonstrate a gross increase in the level of myocardial S-NO, and several specific mitochondrial sites of nitrosylation in heart failure. Future work will investigate the functional consequence of nitrosylation at these sites.

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