Antimycin A induced cardioprotection is dependent on pre-ischemic p38-MAPK activation but independent of MKK3.
To examine the role of mitogen-activated protein kinase kinase 3 (MKK3) and p38 mitogen-activated protein kinase (p38-MAPK) in the cardioprotection afforded by antimycin A. Langendorff perfused murine hearts exposed to antimycin A or vehicle prior to global ischemia with p38-MAPK and HSP27 phosphorylation examined in the presence and absence of SB203580 or the presence (mkk3(+/+)) and absence (mkk3(-/-)) of MKK3. Infarct size was determined after 30 or 40 min of global ischemia and 2 h reperfusion. p38-MAPK dual phosphorylation in response to antimycin A was attenuated by co-administration of the antioxidant mercaptopropyonyl-glycine but unaffected by the absence of MKK3 or the presence of SB203580 at a concentration that inhibited the downstream phosphorylation of HSP27. Pre-ischemic exposure to antimycin A caused a significant reduction in subsequent infarction (I:R%) compared to vehicle on both the mkk3(-/-) and mkk3(+/+) background (23.7+/-2.9 and 22.8+/-4.6 compared to 50.7+/-4.0 and 49.6+/-5.4 P=0.001, respectively). In C57Bl6 mice, antimycin A prior to ischemia reduced infarct size compared to vehicle (22.8 +/- 6.1 vs. 48.3+/-5.2 P=0.01, respectively), an effect abolished by coincident SB203580. The cardiac protection initiated by antimycin A is dependent on the activation of p38-MAPK which occurs, at least in part, in response to oxygen-derived free radicals. The mechanism of this protective form of p38-MAPK activation is independent of the upstream kinase MKK3 and does not involve autophosphorylation.
Kabir
Alamgir M N
AM
Department of Cardiology, The Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
Cao
Xuebin
X
Gorog
Diana A
DA
Tanno
Masaya
M
Bassi
Rehka
R
Bellahcene
Mohamed
M
Quinlan
Roy A
RA
Davis
Roger J
RJ
Flavell
Richard A
RA
Shattock
Michael J
MJ
Marber
Michael S
MS
D000818:Animals; D000968:Antimycin A / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004789:Enzyme Activation; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002316:Cardiotonic Agents; D000968:Antimycin A; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse