Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca2+ Release and Cardiac Contractility, Independently of L-Type Ca2+ Current
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 cAMP levels, phospholamban (PLN) phosphorylation, and SERCA2a activity in SR microdomains.
Methods and Results: We assessed myocardial function in PDE4D-deficient (PDE4D−/−) and littermate wild-type (WT) mice at 10 to 12 weeks of age. Baseline cardiac contractility in PDE4D−/− mice was elevated 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 WT. The protein kinase A inhibitor Rp-adenosine-3′ ,5′ cyclic monophosphorothioate 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 hearts 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 through its interactions with SERCA2a-PLN. Because whole-cell Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
- Received June 11, 2011.
- Revision received August 24, 2011.
- Accepted August 25, 2011.
- © 2011 American Heart Association, Inc.