title: Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction.
abstract: Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO₂ efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO₂ efficiency in septic mice.
authors.affiliation: Département de Physiologie, Faculté de Médecine, Université Lille, 1 Place de Verdun, F-59000 Lille CEDEX 59045, France. rneviere@univ-lille2.fr.|INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France. rneviere@univ-lille2.fr.
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
authors.affiliation: INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France. florian.delguste@univ-lille2.fr.
authors.forename: Florian
authors.initials: F
authors.lastname: Delguste
authors.affiliation: INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France. durand.arthur@gmail.com.|Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France. durand.arthur@gmail.com.
authors.forename: Arthur
authors.initials: A
authors.lastname: Durand
authors.affiliation: Département de Cardiologie, CHU Martinique, Faculté de Médecine, Université des Antilles, F-97200 Fort de France, France. Jocelyn.Inamo@chu-fortdefrance.fr.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Inamo
authors.affiliation: INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France. eric.boulanger@univ-lille2.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Boulanger
authors.affiliation: INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France. seb.preau@gmail.com.|Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France. seb.preau@gmail.com.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Preau
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D019069:Cell Respiration / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D007093:Imidazoles; D024101:Mitochondrial Proteins; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D010768:Phosphoserine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D042967:Electron Transport Complex I; D015056:1-Methyl-3-isobutylxanthine
keywords: cyclic adenosine monophosphate (cAMP); isolated heart; mitochondria respiration; phosphodiesterase; protein kinase A; sepsis; soluble adenylyl cyclase