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The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial KATP channels
Open accessAbstract
The cardioprotective effects of ischemic preconditioning (IPC) can be mimicked or blocked by pharmacologic agents, which modulate the mitochondrial ATP-sensitive potassium (mK(ATP)) channel, thereby implicating this channel in the mechanism of IPC. Cardioprotection can also be achieved via inhibition of mitochondrial respiratory complex II, and significant pharmacologic overlap exists between complex II inhibitors and mK(ATP) channel agonists. However, the relationship between complex II and the mK(ATP) channel remains unclear. Atpenin A5 (AA5) is a potent and specific complex II inhibitor, and herein we report that AA5 (1 nM) also activates the mK(ATP) channel and protects against simulated ischemia-reperfusion (IR) injury in isolated cardiomyocytes. Similar to known mK(ATP) agonists, AA5-mediated protection was sensitive to the mK(ATP) antagonists 5-hydroxydecanoate (5HD) and glyburide. Notably, the optimal mK(ATP) opening and protective concentration of AA5 had no effect on complex II enzymatic activity, suggesting an interaction of AA5 with complex II, but not inhibition of the complex per se, is necessary for protection. A cardioprotective effect of AA5 was also observed in isolated perfused hearts, wherein AA5 increased post-IR contractile function and decreased infarct size, in a 5HD-sensitive manner. In conclusion, the specific complex II inhibitor AA5 is the most potent mK(ATP) activator discovered to date, and provides a novel method of activating mK(ATP) channels and protecting the heart from IR injury.
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“Recently, a model was presented that merges these two conflicting views, i.e. that complex II may be a component or regulator of the mitoK ATP channel [44,156,157].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [44]
In the citing paper
“The effect of atpenin A5 was independent of complex II inhibition, and the authors suggested that opening of the putative mitoK ATP channel is the underlying mechanism.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [44]
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“However, higher concentrations of atpenin A5that were shown to inhibit complex II activityhad to be used in Langendorf-perfused hearts to induce a cardioprotective effect [44].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [44]
In the citing paper
“Importantly, the results of Wojtovich and Brookes indicate that the highly potent and specific complex II inhibitor atpenin A5 had the same cardioprotective effects in cardiomyocytes and Langendorff-perfused rat hearts as ischemic preconditioning, diazoxide, and malonate [44].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [44]
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Cites
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Cardioprotective Effect of Diazoxide and Its Interaction With Mitochondrial ATP-Sensitive K+Channels
Garlid, K., Pauček, P., Yarov-Yarovoy, V. M., Murray, H. N., Darbenzio, R. B., DʼAlonzo, A. J., Lodge, N. J., Smith, M. A., & Grover, G. J. (1997) · Circulation Research · doi:10.1161/01.res.81.6.1072 · Cited by 1,022
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Metadata
- Authors
- Wojtovich, A. P., & Brookes, P. S.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Brookes, Paul S.
- Venue
- Basic Research in Cardiology
- Published
- 2009-02-26
- Volume
- 104
- Issue
- 2
- Pages
- 121-129
- ISSN
- 0003-9217 (ISSN-L)
- 0300-8428
- 1435-1803
- PMC
- PMC2776710
- OpenAlex
- W2092473885
- Cited by
- 107
- References
- 45
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 10 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 8
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Basic Research in Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (R01HL071158)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- complex II inhibition, mitochondrial ATP-sensitive potassium channel, myocardial ischemia-reperfusion injury, cardioprotection, ischemic preconditioning, 5-hydroxydecanoate, glibenclamide, mitochondrial respiration, infarct size, cardiomyocytes
- MeSH terms
- Animals, Anti-Arrhythmia Agents, Decanoic Acids, Hydroxy Acids, Male, Mitochondria, Heart, Pyridones, Potassium Channels, Myocardial Reperfusion Injury, Rats, Sprague-Dawley, Cytoprotection, Myocytes, Cardiac, Electron Transport Complex II, Rats
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