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Updated: Aug 16, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Antimycin A induced cardioprotection is dependent on pre-ischemic p38-MAPK activation but independent of MKK3
Alamgir M N Kabir1, Xuebin Cao, Diana A Gorog
1Department of Cardiology, The Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
Abstract:
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.
Insights
Antimycin A protects the heart from ischemia-reperfusion injury by activating p38-MAPK, independent of MKK3. This cardioprotection relies on p38-MAPK activation, partly due to free radicals.
Area of Science:
- Cardiovascular physiology
- Molecular signaling pathways
- Biochemistry
Background:
- Mitogen-activated protein kinase kinase 3 (MKK3) and p38 mitogen-activated protein kinase (p38-MAPK) are key signaling molecules.
- Antimycin A is known to induce cardioprotection, but the underlying mechanisms involving MKK3 and p38-MAPK require elucidation.
Purpose of the Study:
- To investigate the specific roles of MKK3 and p38-MAPK in antimycin A-mediated cardioprotection.
- To determine if MKK3 is essential for antimycin A-induced p38-MAPK activation and subsequent cardiac protection.
Main Methods:
- Langendorff perfused murine hearts were subjected to global ischemia and reperfusion.
- Hearts were pre-treated with antimycin A or vehicle.
- p38-MAPK and HSP27 phosphorylation were assessed with and without SB203580 (p38-MAPK inhibitor).
- Experiments were conducted in wild-type (mkk3(+/+)) and MKK3-deficient (mkk3(-/-)) mice.
Main Results:
- Antimycin A significantly reduced infarct size in both mkk3(+/+) and mkk3(-/-) hearts.
- p38-MAPK phosphorylation by antimycin A was attenuated by an antioxidant but not by the absence of MKK3.
- SB203580 abolished the infarct-reducing effect of antimycin A, indicating p38-MAPK dependence.
- The protective effect of antimycin A was independent of MKK3 and autophosphorylation.
Conclusions:
- Antimycin A-induced cardioprotection is dependent on p38-MAPK activation.
- This p38-MAPK activation is partly mediated by oxygen-derived free radicals.
- The mechanism of antimycin A-induced p38-MAPK activation and subsequent cardioprotection is independent of MKK3.
