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Mitochondrial nitroalkene formation and mild uncoupling in ischaemic preconditioning: implications for
Sergiy M Nadtochiy1, Paul R S Baker, Bruce A Freeman
1Department of Anesthesiology, Box 604, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Cardiovascular Research
|December 4, 2008
Summary
Ischaemic preconditioning triggers the formation of nitroalkenes, which activate mitochondrial uncoupling via uncoupling proteins (UCPs) and adenine nucleotide translocase (ANT), protecting the heart from injury.
Area of Science:
- Mitochondrial physiology
- Cardioprotection
- Nitric oxide signaling
Background:
- Ischaemic preconditioning (IPC) confers cardioprotection through mechanisms involving mitochondria and nitric oxide (NO*).
- IPC induces mild mitochondrial uncoupling via uncoupling proteins (UCPs) and adenine nucleotide translocase (ANT), which is itself cardioprotective.
- The role of electrophilic lipids, such as nitroalkenes, in IPC-induced mitochondrial uncoupling and cardioprotection remains unclear.
Purpose of the Study:
- To investigate the hypothesis that endogenous formation of NO*-derived electrophilic lipids (nitroalkenes) during IPC stimulates mitochondrial uncoupling.
- To determine if nitroalkenes mediate cardioprotection by post-translational modification of UCPs and ANT.
- To elucidate the role of nitroalkenes in the signalling pathway of ischaemia-reperfusion injury.
Main Methods:
- Langendorff-perfused rat hearts subjected to ischaemic preconditioning (IPC).
- Measurement of endogenous nitroalkene formation using HPLC-ESI-MS/MS.
- Investigation of exogenous nitro-linoleate (LNO2) and biotin-tagged LNO2 effects on isolated heart mitochondria and cardiomyocytes.
Main Results:
- Nitroalkenes, including LNO2, were endogenously generated in mitochondria of IPC hearts.
- Exogenous LNO2 (<1 microM) induced mild mitochondrial uncoupling, inhibited by UCP and ANT inhibitors, and protected cardiomyocytes against simulated ischaemia-reperfusion injury.
- Biotinylated LNO2 covalently modified ANT thiols and potentially UCP-2; no effects were linked to NO* release, cGMP, KATP channels, or kinase signalling.
Conclusions:
- A novel signalling pathway is proposed where IPC-stimulated nitroalkene formation induces mild mitochondrial uncoupling.
- This uncoupling is mediated by post-translational modification of ANT and UCP-2.
- Nitroalkene-induced mitochondrial uncoupling confers resistance to ischaemia-reperfusion injury.
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