title: Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1.
abstract: BACKGROUND
  Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fas-L, or through decreased expression of cyclin D(1).
  
  
  OBJECTIVE
  We tested the hypothesis that hypoxia (HX), angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK, and thus initiating stimulus specific changes in Fas-L and cyclin D(1) expression in failing cardiomyocytes.
  
  
  RESULTS
  Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D(1) detection were performed. HX-induced apoptosis was associated with increased Fas-L expression, A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D(1) expression, and NEPI-induced apoptosis was associated with decreased cyclin D(1) expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D(1) expression.
  
  
  CONCLUSIONS
  HX, A-II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas-L and cyclin D(1) expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D(1).
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, MI 48202, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Anastassia
authors.initials: A
authors.lastname: Todor
authors.forename: George
authors.initials: G
authors.lastname: Suzuki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Tanhehco
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D019938:Cyclin D1 / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D053222:Fas Ligand Protein; D005500:Follow-Up Studies; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D015994:Incidence; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009638:Norepinephrine / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D000804:Angiotensin II; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009638:Norepinephrine