title: Activation of PKN mediates survival of cardiac myocytes in the heart during ischemia/reperfusion.
abstract: BACKGROUND
  The function of PKN, a stress-activated protein kinase, in the heart is poorly understood.
  
  
  OBJECTIVE
  We investigated the functional role of PKN during myocardial ischemia/reperfusion (I/R).
  
  
  RESULTS
  PKN is phosphorylated at Thr774 in hearts subjected to ischemia and reperfusion. Myocardial infarction/area at risk (MI/AAR) produced by 45 minutes of ischemia and 24 hours of reperfusion was significantly smaller in transgenic mice with cardiac-specific overexpression of constitutively active (CA) PKN (Tg-CAPKN) than in nontransgenic (NTg) mice (15+/-5 versus 38+/-5%, P<0.01). The number of TUNEL-positive nuclei was significantly lower in Tg-CAPKN (0.3+/-0.2 versus 1.0+/-0.2%, P<0.05). Both MI/AAR (63+/-9 versus 45+/-8%, P<0.05) and the number of TUNEL-positive cells (7.9+/-1.0 versus 1.3+/-0.9%, P<0.05) were greater in transgenic mice with cardiac-specific overexpression of dominant negative PKN (Tg-DNPKN) than in NTg mice. Thr774 phosphorylation of PKN was also observed in response to H(2)O(2) in cultured cardiac myocytes. Stimulation of PKN prevented, whereas inhibition of PKN aggravated, cell death induced by H(2)O(2), suggesting that the cell-protective effect of PKN is cell-autonomous in cardiac myocytes. PKN induced phosphorylation of alpha B crystallin and increased cardiac proteasome activity. The infarct reducing effect in Tg-CAPKN mice was partially inhibited by epoxomicin, a proteasome inhibitor.
  
  
  CONCLUSIONS
  PKN is activated by I/R and inhibits apoptosis of cardiac myocytes, thereby protecting the heart from I/R injury. PKN mediates phosphorylation of alpha B crystallin and stimulation of proteasome activity, which, in part, mediates the protective effect of PKN in the heart.
authors.affiliation: Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Avenue, Newark, NJ 07103, USA.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takagi
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.forename: Katsuya
authors.initials: K
authors.lastname: Kajimoto
authors.forename: Dan
authors.initials: D
authors.lastname: Shao
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Yang
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Ghassan
authors.initials: G
authors.lastname: Yehia
authors.forename: Chikaomi
authors.initials: C
authors.lastname: Yamada
authors.forename: Daniela
authors.initials: D
authors.lastname: Zablocki
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013912:Threonine; D013997:Time Factors; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: C525420:Cryab protein, mouse; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D038203:alpha-Crystallin B Chain; D013912:Threonine; D006861:Hydrogen Peroxide; C061570:protein kinase N; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin