Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca2+ Release and Cardiac Contractility, Independently of L-Type Ca2+ Current

• Published in: Circulation research 2011-10, Vol.109 (9), p.1024-1030
• Main Authors: Beca, Sanja, Helli, Peter B, Simpson, Jeremy A, Zhao, Dongling, Farman, Gerrie P, Jones, Peter P, Tian, Xixi, Wilson, Lindsay S, Ahmad, Faiyaz, Chen, S.R Wayne, Movsesian, Matthew A, Manganiello, Vincent, Maurice, Donald H, Conti, Marco, Backx, Peter H
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Ca super(2+)-transporting ATPase; Calcium (reticular); Calcium - metabolism; Calcium channels; Calcium channels (L-type); Calcium Channels, L-Type - physiology; Calcium currents; Calcium-Binding Proteins - metabolism; Cardiac muscle; cardiomyocytes; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Cyclic AMP; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Female; Fundamental and applied biological sciences. Psychology; Heart; Heart diseases; Heart Ventricles - metabolism; Heart Ventricles - pathology; Humans; Male; Mice; Mice, Knockout; Models, Animal; Muscle contraction; Myocardial Contraction - physiology; Myocardium; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; phosphatidylinositol; Phosphatidylinositol 3-Kinases - metabolism; phosphodiesterase; Phosphorylation; protein kinase A inhibitors; rolipram; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.250464

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 Ca transient amplitudes and SR Cacontent but unchanged L-type calcium current, compared with littermate controls (WT). The protein kinase A inhibitor Rp-adenosine-3′,5′ cyclic monophosphorothioate (Rp-cAMP) lowered whole-cell Ca transient amplitudes and SR Ca content in PDE4D cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca transients, or SR Ca 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 Ca channels or ryanodine receptor. Because whole-cell Ca transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.