title: Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster.
abstract: OBJECTIVE
  p38 MAP kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) have been implicated in the pathophysiology of heart failure. We investigated the effects of chronic treatment with p38 MAPK and JNK inhibitors on the development of heart failure in dilated cardiomyopathy (DCM) hamster heart.
  
  
  RESULTS
  BIO14.6 hamster hearts showed markedly increased p38 MAPK and JNK activities at 6 weeks of age when there was no significant increase in the area of fibrosis, heart weight/body weight, left ventricular (LV) chamber dilation and LV dysfunction. p38 MAPK and JNK activities were attenuated at 26 weeks of age and abolished at 40 weeks of age in BIO14.6 hamster hearts. BIO14.6 hamsters and the control BIOF1B hamsters were chronically treated (i.p.) with the p38 MAPK inhibitors, SB203580 (1 mg/kg/day) and FR167653 (3 mg/kg/day), or the JNK inhibitor, SP600125 (1 mg/kg/day) or vehicle for 20 weeks starting from 6 weeks of age. Treatment of BIO14.6 hamster hearts with SB203580 and FR167653 reduced the number of TUNEL-positive myocytes, the area of fibrosis and heart weight/body weight associated with a significant decrease of LV dimension and an increase in LV ejection fraction and LV contractility compared to the vehicle-treated counterpart. In contrast, treatment with SP600125 increased the number of TUNEL-positive myocytes and the area of interstitial fibrosis associated with aggravation of LV chamber dilation and LV dysfunction.
  
  
  CONCLUSIONS
  These results suggest that chronic treatment with p38 MAPK and JNK inhibitors produces opposing effects on the development of heart failure in the DCM hamster heart.
authors.affiliation: Cardiovascular Center, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Kyoi
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsuhisa
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Akita
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Chiharu
authors.initials: C
authors.lastname: Enoki
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Hiroji
authors.initials: H
authors.lastname: Imamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamihata
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006224:Cricetinae; D005355:Fibrosis; D007093:Imidazoles / Q000627:therapeutic use*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000873:Anthracenes; C104334:FR 167653; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580