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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn323
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Mitochondrial nitroalkene formation and mild uncoupling in ischemic preconditioning: implications for cardioprotection

Sergiy M. Nadtochiy1,*, Paul R. S. Baker2,*, Bruce A. Freeman2 and Paul S. Brookes1,{dagger}

1 Anesthesiology, University of Rochester Medical Center, Rochester, NY.
2 Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

{dagger} Correspondence to: Paul S. Brookes, PhD., Anesthesiology, Box 604, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Tel: 585-273-1626, Fax: 585-273-2652, paul_brookes{at}urmc.rochester.edu

Aims: Both mitochondria and nitric oxide (NO•) contribute to cardioprotection by ischemic preconditioning (IPC). IPC causes mild uncoupling of mitochondria via uncoupling proteins (UCPs) and the adenine nucleotide translocase (ANT), and mild uncoupling per se is cardioprotective. While electrophilic lipids are known to activate mitochondrial uncoupling, the role of such species in IPC-induced uncoupling and cardioprotection is unclear. We hypothesized that endogenous formation of NO• derived electrophilic lipids (nitroalkenes such as nitro-linoleate, LNO2) during IPC may stimulate mitochondrial uncoupling via post-translational modification of UCPs and ANT, thus affording cardioprotection.

Methods: Hearts from male Sprague-Dawley rats were Langendorff-perfused and subjected to IPC. Nitroalkene formation was measured by HPLC-ESI-MS/MS. The effects of exogenous LNO2 and biotin-tagged LNO2 on isolated heart mitochondria and cardiomyocytes were also investigated.

Results: Nitro-alkenes including LNO2 were endogenously generated in mitochondria of IPC hearts. Synthetic LNO2 (<1 µM) activated mild uncoupling, an effect blocked by UCP and ANT inhibitors. LNO2 (<1 µM) also protected cardiomyocytes against simulated ischemia-reperfusion (SIR) injury. Biotinylated LNO2 covalently modified ANT thiols and possibly UCP-2. No effects of LNO2 were attributable to NO• release, cGMP signaling, mitochondrial KATP channels, or protective kinase signaling.

Conclusions: Components of a novel signaling pathway are inferred, wherein nitroalkenes formed by IPC-stimulated nitration reactions may induce mild mitochondrial uncoupling via post-translational modification of ANT and UCP-2, subsequently conferring resistance to IR injury.

Time for primary review: 10 Days

* Authors contributed equally


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