Title

Protective role of soluble adenylyl cyclase against reperfusion-induced injury of cardiac cells

Document Type

Article

Department

General Surgery (East Africa)

Abstract

Aims:Disturbance of mitochondrial function significantly contributes to the myocardial injury that occursduring reperfusion. Increasing evidence suggests a role of intra-mitochondrial cyclic AMP (cAMP) signaling inpromoting respiration and ATP synthesis. Mitochondrial levels of cAMP are controlled by type 10 solubleadenylyl cyclase (sAC) and phosphodiesterase 2 (PDE2), however their role in the reperfusion-induced injuryremains unknown. Here we aimed to examine whether sAC may support cardiomyocyte survival during re-perfusion.

Methods and results:Adult rat cardiomyocytes or rat cardiac H9C2 cells were subjected to metabolic inhibitionand recovery as a model of simulated ischemia and reperfusion. Cytosolic Ca2+, pH, mitochondrial cAMP (live-cell imaging), and cell viability were analyzed during a 15-min period of reperfusion. Suppression of sAC activityin cardiomyocytes and H9C2 cells, either by sAC knockdown, by pharmacological inhibition or by withdrawal ofbicarbonate, a natural sAC activator, compromised cell viability and recovery of cytosolic Ca2+homeostasisduring reperfusion. Contrariwise, overexpression of mitochondria-targeted sAC in H9C2 cells suppressed re-perfusion-induced cell death. Analyzing cAMP concentration in mitochondrial matrix we found that inhibition ofPDE2, a predominant mitochondria-localized PDE isoform in mammals, during reperfusion significantly in-creased cAMP level in mitochondrial matrix, but not in cytosol. Accordingly, PDE2 inhibition attenuated re-perfusion-induced cardiomyocyte death and improved recovery of the cytosolic Ca2+homeostasis.

Conclusion:sAC plays an essential role in supporting cardiomyocytes viability during reperfusion. Elevation ofmitochondrial cAMP pool either by sAC overexpression or by PDE2 inhibition beneficially affects cardiomyocyte survival during reperfusion

Publication

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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