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Inhibition of p38 MAPK alpha/beta reduces ischemic injury and does not block protective effects of preconditioning
1Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, 27709, USA.
Abstract:
We examined the effect of inhibition of p38 mitogen-activated protein kinase (MAPK) alpha/beta during ischemia and preconditioning by using the inhibitor SB-202190. Isolated rat hearts were perfused with Krebs-Henseleit buffer, while left ventricular developed pressure (LVDP) and (31)P nuclear magnetic resonance spectra were acquired continuously. After 20 min of ischemia and 25 min of reperfusion, recovery of LVDP in untreated hearts was 32 +/- 4%, whereas hearts treated with SB-202190 5 min before ischemia recovered 59 +/- 7% of their pretreatment LVDP. Preconditioning improved functional recovery to 65 +/- 5%, which was unaffected by SB-202190 treatment, added either throughout the preconditioning protocol (56 +/- 5% recovery) or during the final reperfusion period of preconditioning (71 +/- 11% recovery). Necrosis was assessed after 40 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining and creatine kinase release. The untreated group had 54 +/- 8% necrotic myocardium, whereas the SB-202190-treated group had 32 +/- 7% and the preconditioned group had 21 +/- 4% necrotic tissue by TTC staining.
Insights
Inhibiting p38 mitogen-activated protein kinase (MAPK) alpha/beta with SB-202190 significantly improved heart function and reduced tissue damage after ischemia. This suggests p38 MAPK alpha/beta is a key target for cardioprotection.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Ischemia-reperfusion injury remains a critical challenge in cardiovascular disease.
- p38 mitogen-activated protein kinase (MAPK) alpha/beta signaling pathways are implicated in cardiac stress responses.
- Understanding the role of p38 MAPK alpha/beta in myocardial protection is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting p38 MAPK alpha/beta using SB-202190 during ischemia and preconditioning.
- To assess the impact of SB-202190 on cardiac function and myocardial necrosis following ischemic events.
- To determine if SB-202190 modulates the protective effects of preconditioning.
Main Methods:
- Isolated rat hearts were subjected to ischemia and reperfusion protocols.
- The p38 MAPK alpha/beta inhibitor SB-202190 was administered before ischemia or during preconditioning.
- Cardiac function was assessed by measuring left ventricular developed pressure (LVDP).
- Myocardial necrosis was quantified using 2,3,5-triphenyltetrazrazolium chloride (TTC) staining and creatine kinase release.
Main Results:
- SB-202190 treatment significantly improved LVDP recovery (59% vs. 32%) and reduced myocardial necrosis (32% vs. 54%) after ischemia compared to untreated hearts.
- Preconditioning enhanced functional recovery (65%) and reduced necrosis (21%), with SB-202190 not significantly altering these protective effects.
- SB-202190 administration during preconditioning or reperfusion did not abolish the benefits of preconditioning.
Conclusions:
- Inhibition of p38 MAPK alpha/beta with SB-202190 demonstrates significant cardioprotective effects against ischemia-reperfusion injury.
- p38 MAPK alpha/beta plays a critical role in mediating cardiac damage during ischemia.
- Targeting p38 MAPK alpha/beta represents a promising therapeutic strategy for myocardial protection, potentially in conjunction with preconditioning protocols.
