Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

• DOI: 10.1073/pnas.1416230112
• Publication Date: 2015-04-16T03:32:39Z
• Authors: Youn Wook Chung; Claudia Lagranha; Yong Chen; Junhui Sun; Guang Tong; Steven C. Hockman; Faiyaz Ahmad; Shervin G. Esfahani; Dahae H. Bae; Nazari Polidovitch; Jian Wu; Dong Keun Rhee; Beom Seob Lee; Marjan Gucek; Mathew P. Daniels; Christine A. Bran...; Peter H. Backx; Elizabeth Murphy; Vincent C. Mangan...
• Keywords: Myocardium/pathology; 0301 basic medicine; Myocardial Infarction/pathology; Myocardial Infarction/genetics; Myocardial Reperfusion Injury*/genetics; Caveolin 3; Phosphodiesterase Inhibitors; Caveolin 3/metabolism; Mitochondrial Membrane Transport Proteins/pharmacology; Myocardial Infarction; Quinolones; Myocardium/enzymology*; ischemia/reperfusion injury; Mitochondrial Membrane Transport Proteins; Mitochondria, Heart; Mice; Cyclic AMP; Cyclic AMP/genetics; Cyclic AMP/metabolism; Myocardial Reperfusion Injury*/pathology; Mice, Knockout; Heart/metabolism; Myocardial Reperfusion Injury*/prevention & control; Connexin 43/genetics; Heart/pathology; Mitochondria; Type 3/deficiency*; Mitochondrial Membrane Transport Proteins/metabolism; Phosphodiesterase Inhibitors/pharmacology; Cyclic Nucleotide Phosphodiesterases; Heart/genetics; 570; Knockout; 610; Myocardial Reperfusion Injury; PDE3B−/− mice; Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism; Myocardial Infarction/enzymology; Type 3/metabolism; 03 medical and health sciences; Myocardial Reperfusion Injury*/enzymology; Animals; Mitochondrial Permeability Transition Pore; Myocardium; signalosome; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; Caveolin 3/genetics; membrane repair; Connexin 43; Myocardial Infarction/prevention & control; Quinolones/pharmacology; Mitochondrial Membrane Transport Proteins/genetics; protein kinase A; Connexin 43/metabolism

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor underlying mechanisms have identified. Targeted disruption subfamily B (PDE3B), but not A (PDE3A), protected mouse from I/R injury in vivo and vitro, with reduced infarct size improved cardiac function. The cardioprotective effect PDE3B(-/-) was reversed by blocking cAMP-dependent PKA paxilline, an inhibitor mitochondrial calcium-activated K channels, opening which is potentiated cAMP/PKA signaling. Compared WT mitochondria, mitochondria were enriched antiapoptotic Bcl-2, produced less reactive oxygen species, more frequently contacted transverse tubules where PDE3B localized caveolin-3. Moreover, a fraction containing connexin-43 caveolin-3 resistant Ca(2+)-induced permeability transition pore. Proteomics analyses indicated that fractions buoyant ischemia-induced caveolin-3-enriched (ICEFs) proteins. Accumulation proteins into ICEFs dependent achieved ischemic preconditioning or treatment cilostamide. Taken together, these findings indicate deletion confers effects because cAMP/PKA-induced preconditioning, associated accumulation function ICEFs. To our knowledge, study first define role for cardioprotection suggests as target cardiovascular therapies.