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Published on: June 3, 2018
Role of p38 mitogen-activated protein kinase in cardiac remodelling
1Medizinische Klinik und Poliklinik I, Herz-/ Kreislaufzentrum, Universität Würzburg, Germany. frantz_s@medizin.uni-wuerzburg.de
Background And Purpose:
Mitogen-activated protein kinases (MAPK) are centrally involved in several mechanisms important for heart failure such as apoptosis, activation of inflammatory responses and cell proliferation. We therefore evaluated the effect of the selective p38 MAPK inhibitor SB 239063 on progression of left ventricular remodelling after myocardial infarction (MI) in rats.
Experimental Approach:
Rats were treated for 9 weeks with placebo or SB 239063 by gavage (15 mg kg(-1)) twice daily starting 7 days after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at days 7, 36 and 70.
Key Results:
Over the 9 weeks, mortality was not different between the groups. On echocardiography, animals after myocardial infarction exhibited significant left ventricular dilatation as expected (week 10, end-systolic diameter, placebo sham 5.21+/- 0.34 vs. placebo MI 8.44+/- 0.57 mm). However, there was no difference between placebo and SB 239063-treated rats (week 10, end-systolic diameter, SB MI 7.76+/- 0.74 mm, not significantly different from placebo MI). Haemodynamics changed accordingly. Moreover, SB 239063 had no effect on left ventricular hypertrophy. Treatment with SB 239063 significantly reduced cytokine expression of tumour necrosis factor and interleukin-1beta after myocardial infarction. However, collagen content was not influenced by the treatment.
Conclusion:
Despite a reduction of inflammation, treatment with the p38 inhibitor SB 239063 does not affect cardiac remodelling and cardiac function when treatment is started 7 days after myocardial infarction.
Insights
Selective p38 MAPK inhibition with SB 239063 did not improve cardiac remodelling after myocardial infarction in rats. Despite reducing inflammation, this treatment did not alter heart function or structure post-MI.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Mitogen-activated protein kinases (MAPK) play key roles in heart failure mechanisms, including apoptosis and inflammation.
- p38 MAPK is a critical signaling pathway implicated in cardiac dysfunction.
Purpose of the Study:
- To investigate the therapeutic potential of SB 239063, a selective p38 MAPK inhibitor, on left ventricular remodeling post-myocardial infarction (MI).
Main Methods:
- Rats underwent myocardial infarction (MI) and were treated with SB 239063 or placebo for 9 weeks.
- Transthoracic echocardiography was used to assess cardiac structure and function at multiple time points.
- Cytokine expression and collagen content were analyzed post-treatment.
Main Results:
- SB 239063 treatment did not significantly alter mortality, left ventricular dilatation, or hypertrophy compared to placebo.
- While SB 239063 reduced pro-inflammatory cytokine expression (TNF, IL-1beta), it did not impact collagen content.
- Cardiac function and hemodynamics remained unchanged in the treated group.
Conclusions:
- Late-stage administration of the p38 MAPK inhibitor SB 239063 does not attenuate cardiac remodeling or improve function after myocardial infarction in rats.
- Targeting p38 MAPK inflammation pathways after established MI may not be a viable therapeutic strategy for preventing adverse cardiac remodeling.
