Role of p38 mitogen-activated protein kinase in cardiac remodelling.
OBJECTIVE
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.


METHODS
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.


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.


CONCLUSIONS
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.
Frantz
S
S
Medizinische Klinik und Poliklinik I, Herz-/ Kreislaufzentrum, Universität Würzburg, Germany. frantz_s@medizin.uni-wuerzburg.de
Behr
T
T
Hu
K
K
Fraccarollo
D
D
Strotmann
J
J
Goldberg
E
E
Ertl
G
G
Angermann
C E
CE
Bauersachs
J
J
D000818:Animals; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000401:mortality / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014463:Ultrasonography; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D007093:Imidazoles; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063