title: Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury.
abstract: 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.
authors: Cardiovascular and Pulmonary Branch, Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; chungyw@yuhs.ac manganiv@nhlbi.nih.gov.
authors: Youn Wook
authors: YW
authors: Chung
authors: Systems Biology Center.
authors: Claudia
authors: C
authors: Lagranha
authors: Proteomics Core Facility, and.
authors: Yong
authors: Y
authors: Chen
authors: Systems Biology Center.
authors: Junhui
authors: J
authors: Sun
authors: Systems Biology Center, Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, China;
authors: Guang
authors: G
authors: Tong
authors: Cardiovascular and Pulmonary Branch.
authors: Steven C
authors: SC
authors: Hockman
authors: Cardiovascular and Pulmonary Branch.
authors: Faiyaz
authors: F
authors: Ahmad
authors: Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Shervin G
authors: SG
authors: Esfahani
authors: Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Dahae H
authors: DH
authors: Bae
authors: Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 3A8, Canada;
authors: Nazari
authors: N
authors: Polidovitch
authors: Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 3A8, Canada;
authors: Jian
authors: J
authors: Wu
authors: Cardiovascular and Pulmonary Branch.
authors: Dong Keun
authors: DK
authors: Rhee
authors: Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; Graduate Program in Science for Aging, Yonsei University, Seoul 120-752, Korea; and.
authors: Beom Seob
authors: BS
authors: Lee
authors: Proteomics Core Facility, and.
authors: Marjan
authors: M
authors: Gucek
authors: Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Mathew P
authors: MP
authors: Daniels
authors: Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors: Christine A
authors: CA
authors: Brantner
authors: Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 3A8, Canada; Division of Cardiology, University Health Network, Toronto, ON M5S 3E2, Canada.
authors: Peter H
authors: PH
authors: Backx
authors: Systems Biology Center.
authors: Elizabeth
authors: E
authors: Murphy
authors: Cardiovascular and Pulmonary Branch, chungyw@yuhs.ac manganiv@nhlbi.nih.gov.
authors: Vincent C
authors: VC
authors: Manganiello
mesh_terms: D000818:Animals; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology
chemical_list: C495548:Cav3 protein, mouse; D051244:Caveolin 3; D018031:Connexin 43; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; C021294:cilostamide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517289:Pde3a protein, mouse; C517293:Pde3b protein, mouse
keywords: PDE3B−/− mice; ischemia/reperfusion injury; membrane repair; protein kinase A; signalosome