title: p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart.
abstract: BACKGROUND
  Increasing evidence suggests that development of heart failure involves activation of stress-response inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6. Yet, the myocyte contribution to their induction in failing hearts and the underlying regulatory mechanism in stressed myocardium remain unclear.
  
  
  RESULTS
  In cultured cardiac myocytes, specific activation of stress-activated mitogen-activated protein kinase, p38, by upstream activator MKK6bE led to significant induction of tumor necrosis factor-alpha and interleukin-6 secretion, whereas treating cells with a selective p38 inhibitor (SB239068) significantly blocked the cytokine secretion from myocytes and increased their intracellular accumulation. Targeted expression of MKK6bE in transgenic hearts also resulted in a marked elevation in plasma tumor necrosis factor-alpha and interleukin-6; oral administration of SB239068 resulted in a significant reduction in their plasma levels but an increase in intracardiac accumulation of both cytokines. MKK6bE transgenic hearts developed marked interstitial fibrosis with increased matrix metalloproteinase abundance and selective induction of tissue inhibitor of matrix metalloproteinase-1; this extracellular matrix remodeling was also significantly attenuated by p38 inhibition. Along with cytokine induction and extracellular remodeling, MKK6bE transgenic animals displayed impaired hemodynamic function, whereas p38 inhibition improved the cardiac performance and prolonged the survival of the animals.
  
  
  CONCLUSIONS
  Stress-activated p38 kinase is a critical regulator of inflammatory response in cardiomyocytes with significant contribution to pathological remodeling in stressed myocardium. Inhibition of p38 may represent a useful therapeutic avenue to ameliorate cardiac pathology and heart failure evolution.
authors.affiliation: Department of Physiology, University of Maryland, School of Medicine, Baltimore, USA.
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Georgakopoulos
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Lisa
authors.initials: L
authors.lastname: Hester
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Jeffery
authors.initials: J
authors.lastname: Hasday
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases