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.

Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments

“…In alignment with these results, a recent report suggested that PDE2 inhibition has a protective effect in a brain ischemia/reperfusion model, although it was delayed rather than acute effects of reperfusion that were analyzed [ 123 ]. Similarly, an inhibition of matrix localized PDE2A with BAY60-7550 reduced the uncoupled respiration rate and increased cytochrome c oxidase activity in septic mice [ 124 ].…”

Involvement of Mitochondrial Disorders in Septic Cardiomyopathy

“…The mitochondrial cAMP-PKA pathway couples the Krebs cycle and OXPHOS activity to generate ATP. In a mouse model of acute peritonitis, Neviere et al observed that sepsis-related cardiomyopathy was associated with impaired cAMP-PKA signaling, decreased complex IV phosphorylation of serine 58, decreased mitochondrial RCR, and left ventricle contractile dysfunction [ 51 ]. Ex vivo inhibition of phosphodiesterase 2A by mitochondria-permeant Bay 607550 prevented mitochondrial cAMP depletion, complex IV phosphorylation, OXPHOS uncoupling, and contractile dysfunction.…”

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

“…Furthermore, Neviere et al, indicated that PDE2 inhibition in septic cardiac fibers was beneficial as it limited sepsis-induced myocardial dysfunction and improved mitochondrial respiration [ 194 ]. Since sAC-induced cytochrome c oxidase phosphorylation is PKA-dependent, PDE2 inhibition partially increased cytochrome c oxidase subunit IV-1 protein phosphorylation in septic cardiac fibers.…”

“…Moreover, perfusion of isolated septic hearts with the PDE2 inhibitor BAY60-7550 increased left ventricular developed force. Consistently, pretreatment with BAY60-7550, prior to a cecal ligation puncture procedure to induce sepsis, also significantly reduced coronary perfusion pressure and improved cardiac efficiency in septic mice in vivo [ 194 ]. Collectively, PDE2 inhibition improves myocardial function in septic hearts by maintaining endothelial barrier integrity and improving mitochondrial respiration.…”