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Int. J. Mol. Sci. 2016, 17(12), 2075; doi:10.3390/ijms17122075

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

1
Département de Physiologie, Faculté de Médecine, Université Lille, 1 Place de Verdun, F-59000 Lille CEDEX 59045, France
2
INSERM LIRIC U995/Team “Glycation: From Inflammation to Aging”, Université Lille, F-59000 Lille, France
3
Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France
4
Département de Cardiologie, CHU Martinique, Faculté de Médecine, Université des Antilles, F-97200 Fort de France, France
*
Author to whom correspondence should be addressed.
Academic Editors: Patricia Renard, Michel Jadot, Thierry Arnould and Anthony Lemarié
Received: 14 September 2016 / Revised: 18 November 2016 / Accepted: 6 December 2016 / Published: 10 December 2016
(This article belongs to the Special Issue Mitochondria Crosstalks with other Organelles in Pathophysiology)
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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. View Full-Text
Keywords: mitochondria respiration; cyclic adenosine monophosphate (cAMP); protein kinase A; soluble adenylyl cyclase; phosphodiesterase; isolated heart; sepsis mitochondria respiration; cyclic adenosine monophosphate (cAMP); protein kinase A; soluble adenylyl cyclase; phosphodiesterase; isolated heart; sepsis
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MDPI and ACS Style

Neviere, R.; Delguste, F.; Durand, A.; Inamo, J.; Boulanger, E.; Preau, S. Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction. Int. J. Mol. Sci. 2016, 17, 2075.

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