Sanja Beca1,2, Peter B Helli1,2, Jeremy A Simpson1,2, Dongling Zhao1,2, Gerrie P Farman1,2, Peter Jones3, Xixi Tian3, Lindsay S Wilson4, Faiyaz Ahmad5, S R Wayne Chen3, Matthew A Movsesian6, Vincent Manganiello5, Donald H Maurice4,7, Marco Conti8, Peter H Backx1,9,10,2. 1. Department of Physiology, University of Toronto. 2. Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto. 3. Department of Physiology and Biophysics, University of Calgary. 4. Department of Pathology and Molecular Medicine, Queen's University, Kingston. 5. The Cardiovascular Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda. 6. VA Salt Lake City Health Care System and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah. 7. Department of Pharmacology and Toxicology, Queen's University, Kingston. 8. Department of Obstetrics and Gynaecology, University of California San Francisco. 9. Department of Medicine, University of Toronto. 10. Division of Cardiology at the University Health Network, University of Toronto.
Abstract
RATIONALE: Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ-dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a). OBJECTIVE: The goal of this study was to determine whether PDE4D regulates basal cardiac contractility. METHODS AND RESULTS: At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D(-/-)) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D(-/-) cardiomyocytes showed increased whole-cell Ca2+ transient amplitudes and SR Ca2+content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor R(p)-adenosine-3',5' cyclic monophosphorothioate (R(p)-cAMP) lowered whole-cell Ca2+ transient amplitudes and SR Ca2+ content in PDE4D(-/-) cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca2+ transients, or SR Ca2+ content in PDE4D(-/-) preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D(-/-). The functional changes in PDE4D(-/-) myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D(-/-) cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. CONCLUSIONS: PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca2+ channels or ryanodine receptor. Because whole-cell Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
RATIONALE: Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ-dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase type 2a (SERCA2a). OBJECTIVE: The goal of this study was to determine whether PDE4D regulates basal cardiac contractility. METHODS AND RESULTS: At 10 to 12 weeks of age, baseline cardiac contractility in PDE4D-deficient (PDE4D(-/-)) mice was elevated mice in vivo and in Langendorff perfused hearts, whereas isolated PDE4D(-/-) cardiomyocytes showed increased whole-cell Ca2+ transient amplitudes and SR Ca2+content but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor R(p)-adenosine-3',5' cyclic monophosphorothioate (R(p)-cAMP) lowered whole-cell Ca2+ transient amplitudes and SR Ca2+ content in PDE4D(-/-) cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca2+ transients, or SR Ca2+ content in PDE4D(-/-) preparations but increased these parameters in WT myocardium to levels indistinguishable from those in PDE4D(-/-). The functional changes in PDE4D(-/-) myocardium were associated with increased PLN phosphorylation but not cardiac ryanodine receptor phosphorylation. Rolipram increased PLN phosphorylation in WT cardiomyocytes to levels indistinguishable from those in PDE4D(-/-) cardiomyocytes. In murine and failing human hearts, PDE4D coimmunoprecipitated with SERCA2a but not with cardiac ryanodine receptor. CONCLUSIONS:PDE4D regulates basal cAMP levels in SR microdomains containing SERCA2a-PLN, but not L-type Ca2+ channels or ryanodine receptor. Because whole-cell Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
Authors: Michael A Crackower; Gavin Y Oudit; Ivona Kozieradzki; Renu Sarao; Hui Sun; Takehiko Sasaki; Emilio Hirsch; Akira Suzuki; Tetsuo Shioi; Junko Irie-Sasaki; Rajan Sah; Hai-Ying M Cheng; Vitalyi O Rybin; Giuseppe Lembo; Luigi Fratta; Antonio J Oliveira-dos-Santos; Jeffery L Benovic; C Ronald Kahn; Seigo Izumo; Susan F Steinberg; Matthias P Wymann; Peter H Backx; Josef M Penninger Journal: Cell Date: 2002-09-20 Impact factor: 41.582
Authors: F del Monte; E Williams; D Lebeche; U Schmidt; A Rosenzweig; J K Gwathmey; E D Lewandowski; R J Hajjar Journal: Circulation Date: 2001-09-18 Impact factor: 29.690
Authors: M Packer; J R Carver; R J Rodeheffer; R J Ivanhoe; R DiBianco; S M Zeldis; G H Hendrix; W J Bommer; U Elkayam; M L Kukin Journal: N Engl J Med Date: 1991-11-21 Impact factor: 91.245
Authors: Donald H Maurice; Hengming Ke; Faiyaz Ahmad; Yousheng Wang; Jay Chung; Vincent C Manganiello Journal: Nat Rev Drug Discov Date: 2014-04 Impact factor: 84.694
Authors: Tatiana M Vinogradova; Syevda Sirenko; Yevgeniya O Lukyanenko; Dongmei Yang; Kirill V Tarasov; Alexey E Lyashkov; Nevin J Varghese; Yue Li; Khalid Chakir; Bruce Ziman; Edward G Lakatta Journal: Circ Arrhythm Electrophysiol Date: 2018-06
Authors: Li Wang; Brian T Burmeister; Keven R Johnson; George S Baillie; Andrei V Karginov; Randal A Skidgel; John P O'Bryan; Graeme K Carnegie Journal: Cell Signal Date: 2015-02-12 Impact factor: 4.315