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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.
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Soumis le : mercredi 18 mars 2020 - 11:33:34
Dernière modification le : mercredi 9 décembre 2020 - 10:54:11


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Rémi Nevière, Florian Delguste, Arthur Durand, Jocelyn Inamo, Eric Boulanger, et al.. Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction.. International Journal of Molecular Sciences, MDPI, 2016, 17 (12), pp.2075. ⟨10.3390/ijms17122075⟩. ⟨hal-02506368⟩



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