title: cGMP-dependent protein kinase type I inhibits TAB1-p38 mitogen-activated protein kinase apoptosis signaling in cardiac myocytes.
abstract: Cardiac myocyte apoptosis during ischemia and reperfusion (I/R) is tightly controlled by a complex network of stress-responsive signaling pathways. One pro-apoptotic pathway involves the interaction of the scaffold protein TAB1 with p38 mitogen-activated protein kinase (p38 MAPK) leading to the autophosphorylation and activation of p38 MAPK. Conversely, NO and its second messenger cGMP protect cardiac myocytes from apoptosis during I/R. We provide evidence that the cGMP target cGMP-dependent protein kinase type I (PKG I) interferes with TAB1-p38 MAPK signaling to protect cardiac myocytes from I/R injury. In isolated neonatal cardiac myocytes, activation of PKG I inhibited the interaction of TAB1 with p38 MAPK, p38 MAPK phosphorylation, and apoptosis induced by simulated I/R. During I/R in vivo, mice with a cardiac myocyte-restricted deletion of PKG I displayed a more pronounced interaction of TAB1 with p38 MAPK and a stronger phosphorylation of p38 MAPK in the myocardial area at risk during reperfusion and more apoptotic cardiac myocytes in the infarct border zone as compared with wild-type littermates. Notably, adenoviral expression of a constitutively active PKG I mutant truncated at the N terminus(PKGI-DeltaN1-92) did not inhibit p38 MAPK phosphorylation and apoptosis induced by simulated I/R in vitro, indicating that the N terminus of PKG I is required. As shown by co-immunoprecipitation experiments in HEK293 cells, cGMP-activated PKG I, but not constitutively active PKG I-DeltaN1-92 or PKG I mutants carrying point mutations in the N-terminal leucine-isoleucine zipper, interacted with p38 MAPK, and prevented the binding of TAB1 to p38 MAPK. Together, our data identify a novel interaction between the cGMP target PKG I and the TAB1-p38 MAPK signaling pathway that serves as a defense mechanism against myocardial I/R injury.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Fiedler
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Christian
authors.initials: C
authors.lastname: Willenbockel
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Albert
authors.initials: A
authors.lastname: Smolenski
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Lohmann
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000494:pharmacology*; D004789:Enzyme Activation; D006352:Heart Ventricles / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C099510:TAB1 protein, MAPKKK activator, vertebrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases