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Updated: Aug 29, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia
Diana A Gorog1, Masaya Tanno, Xuebin Cao
1Division of Cardiology, KCL, The Rayne Institute, St. Thomas' Hospital, London, UK.
Objective:
The basal activity of p38 MAPK has recently been shown to impair myocardial contractility. This kinase is activated by ischemia and short-term hibernation. We hypothesized that p38 MAPK activation may contribute to the contractile deficit that characterizes low-flow ischemia.
Methods:
In Langendorff-perfused isolated C57BL/6 mouse hearts, perfusion pressure was reduced from 85 to 15 or 30 mm Hg for 120 min to induce ischemic left ventricular dysfunction. The effect of the p38 MAPK inhibitor SB203580 (1 microM/l) on contractile function and p38 MAPK activation was assessed.
Results:
Reduction in perfusion pressure to 15 or 30 mm Hg was accompanied by stable reductions in coronary flow (83+/-2% and 66+/-2%, respectively) and developed pressure (84+/-2% and 61+/-3%), with minimal infarction (15.6+/-0.69% and 10.6+/-0.98% of LV myocardium, respectively), but marked activation of p38 MAPK (reflected in pHSP27 1092+/-326% basal and 996+/-301% basal, respectively). The p38 MAPK inhibitor SB203580, present during the last 60 min of reduced pressure perfusion, prevented p38 MAPK activation (pHSP27 281+/-92% basal, p=0.01 and 186+/-72% basal, p=0.01) but, despite the presence of a contractile reserve, had no effect on developed pressure. Similarly, early treatment with SB203580 started 5 min after the onset of reduced flow also failed to attenuate contractile dysfunction.
Conclusion:
The p38 MAPK activation that accompanies short-term hibernation does not appear to contribute to the contractile deficit.
Insights
p38 mitogen-activated protein kinase (MAPK) activation during low-flow ischemia in mouse hearts did not worsen contractile dysfunction. Inhibiting p38 MAPK did not improve cardiac function, suggesting it does not cause contractile deficits in short-term hibernation.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Ischemic Heart Disease
Background:
- Basal activity of p38 MAPK impairs myocardial contractility.
- p38 MAPK is activated by ischemia and short-term hibernation.
- Low-flow ischemia causes a contractile deficit in the heart.
Purpose of the Study:
- To investigate if p38 MAPK activation contributes to the contractile deficit during low-flow ischemia.
- To assess the effect of a p38 MAPK inhibitor on ischemic left ventricular dysfunction.
Main Methods:
- Isolated C57BL/6 mouse hearts were Langendorff-perfused.
- Perfusion pressure was reduced to induce ischemic left ventricular dysfunction.
- The p38 MAPK inhibitor SB203580 was used to assess its effect on contractile function and p38 MAPK activation.
Main Results:
- Reduced perfusion pressure caused stable reductions in coronary flow and developed pressure with minimal infarction.
- Marked activation of p38 MAPK was observed during reduced perfusion pressure.
- SB203580 prevented p38 MAPK activation but did not improve developed pressure or attenuate contractile dysfunction.
Conclusions:
- p38 MAPK activation during short-term hibernation does not appear to contribute to the contractile deficit.
- Inhibition of p38 MAPK does not ameliorate contractile dysfunction in this model.
