PMID- 19242645
OWN - NLM
STAT- MEDLINE
DCOM- 20090519
LR  - 20211020
IS  - 1435-1803 (Electronic)
IS  - 0300-8428 (Print)
IS  - 0300-8428 (Linking)
VI  - 104
IP  - 2
DP  - 2009 Mar
TI  - The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion 
      injury via activation of mitochondrial KATP channels.
PG  - 121-9
LID - 10.1007/s00395-009-0001-y [doi]
AB  - 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.
FAU - Wojtovich, Andrew P
AU  - Wojtovich AP
AD  - Department of Pharmacology and Physiology, University of Rochester Medical 
      Center, Rochester, NY, USA.
FAU - Brookes, Paul S
AU  - Brookes PS
LA  - eng
GR  - R01 HL071158/HL/NHLBI NIH HHS/United States
GR  - R01 HL071158-06A1/HL/NHLBI NIH HHS/United States
GR  - R01-HL071158/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090226
PL  - Germany
TA  - Basic Res Cardiol
JT  - Basic research in cardiology
JID - 0360342
RN  - 0 (Anti-Arrhythmia Agents)
RN  - 0 (Decanoic Acids)
RN  - 0 (Hydroxy Acids)
RN  - 0 (Potassium Channels)
RN  - 0 (Pyridones)
RN  - 0 (mitochondrial K(ATP) channel)
RN  - 0 (respiratory complex II)
RN  - 119509-24-9 (atpenin A5)
RN  - 624-00-0 (5-hydroxydecanoic acid)
RN  - EC 1.3.5.1 (Electron Transport Complex II)
SB  - IM
MH  - Animals
MH  - Anti-Arrhythmia Agents/pharmacology
MH  - Cytoprotection
MH  - Decanoic Acids/pharmacology
MH  - Electron Transport Complex II/drug effects/metabolism
MH  - Hydroxy Acids/pharmacology
MH  - Male
MH  - Mitochondria, Heart/*drug effects/*metabolism
MH  - Myocardial Reperfusion Injury/*prevention & control
MH  - Myocytes, Cardiac/drug effects/metabolism
MH  - Potassium Channels/*drug effects/*metabolism
MH  - Pyridones/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC2776710
MID - NIHMS156519
EDAT- 2009/02/27 09:00
MHDA- 2009/05/20 09:00
PMCR- 2010/03/01
CRDT- 2009/02/27 09:00
PHST- 2008/11/17 00:00 [received]
PHST- 2009/01/18 00:00 [accepted]
PHST- 2009/01/12 00:00 [revised]
PHST- 2009/02/27 09:00 [entrez]
PHST- 2009/02/27 09:00 [pubmed]
PHST- 2009/05/20 09:00 [medline]
PHST- 2010/03/01 00:00 [pmc-release]
AID - 10.1007/s00395-009-0001-y [doi]
PST - ppublish
SO  - Basic Res Cardiol. 2009 Mar;104(2):121-9. doi: 10.1007/s00395-009-0001-y. Epub 
      2009 Feb 26.