Phosphodiesterase 4D Regulates Baseline Sarcoplasmic Reticulum Ca ²⁺ Release and Cardiac Contractility, Independently of L-Type Ca ²⁺ 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 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 2+ transient amplitudes and SR Ca 2+ 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 Ca 2+ transient amplitudes and SR Ca 2+ content in PDE4D −/− cardiomyocytes to WT levels. The PDE4 inhibitor rolipram had no effect on cardiac contractility, whole-cell Ca 2+ transients, or SR Ca 2+ 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 2+ channels or ryanodine receptor. Because whole-cell Ca 2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.