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

 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. Brantner  ;  Peter H. Backx  ;  Elizabeth Murphy  ;  Vincent C. Manganiello 
 Proceedings of the National Academy of Sciences of the United States of America, Vol.112(17) : E2253-E2262, 2015 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
Issue Date
Animals ; Caveolin 3/genetics ; Caveolin 3/metabolism ; Connexin 43/genetics ; Connexin 43/metabolism ; Cyclic AMP/genetics ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/deficiency* ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Mice ; Mice, Knockout ; Mitochondria, Heart/genetics ; Mitochondria, Heart/metabolism ; Mitochondria, Heart/pathology ; Mitochondrial Membrane Transport Proteins/genetics ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Membrane Transport Proteins/pharmacology ; Myocardial Infarction/enzymology ; Myocardial Infarction/genetics ; Myocardial Infarction/pathology ; Myocardial Infarction/prevention & control ; Myocardial Reperfusion Injury*/enzymology ; Myocardial Reperfusion Injury*/genetics ; Myocardial Reperfusion Injury*/pathology ; Myocardial Reperfusion Injury*/prevention & control ; Myocardium/enzymology* ; Myocardium/pathology ; Phosphodiesterase Inhibitors/pharmacology ; Quinolones/pharmacology
PDE3B−/− mice ; ischemia/reperfusion injury ; membrane repair ; protein kinase A ; signalosome
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 the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected mouse heart from I/R injury in vivo and in vitro, with reduced infarct size and improved cardiac function. The cardioprotective effect in PDE3B(-/-) heart was reversed by blocking cAMP-dependent PKA and by paxilline, an inhibitor of mitochondrial calcium-activated K channels, the opening of which is potentiated by cAMP/PKA signaling. Compared with WT mitochondria, PDE3B(-/-) mitochondria were enriched in antiapoptotic Bcl-2, produced less reactive oxygen species, and more frequently contacted transverse tubules where PDE3B was localized with caveolin-3. Moreover, a PDE3B(-/-) mitochondrial fraction containing connexin-43 and caveolin-3 was more resistant to Ca(2+)-induced opening of the mitochondrial permeability transition pore. Proteomics analyses indicated that PDE3B(-/-) heart mitochondria fractions were enriched in buoyant ischemia-induced caveolin-3-enriched fractions (ICEFs) containing cardioprotective proteins. Accumulation of proteins into ICEFs was PKA dependent and was achieved by ischemic preconditioning or treatment of WT heart with the PDE3 inhibitor cilostamide. Taken together, these findings indicate that PDE3B deletion confers cardioprotective effects because of cAMP/PKA-induced preconditioning, which is associated with the accumulation of proteins with cardioprotective function in ICEFs. To our knowledge, our study is the first to define a role for PDE3B in cardioprotection against I/R injury and suggests PDE3B as a target for cardiovascular therapies.
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Chung, Youn Wook(정연욱) ORCID logo https://orcid.org/0000-0002-4382-1410
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