Abstract 20418: Phosphodiesterase 4D (PDE4D) Enhances Myocardial Contractility by Regulating Sarcoplasmic Reticulum Ca2+ Load
Objective: To determine whether PDE4D is the PDE4 isozyme that locally regulates cAMP in SERCA-2a regions.
Methods & Results: Cardiac function (in vivo and Langendorff hearts) was assessed in 10–12 week old wild-type (WT) and PDE4D deficient (PDE4D−/−) mice. L-type calcium currents (ICaL), Ca2+ transients and SR Ca2+ loads were measured in voltage-clamped isolated cardiomyocytes while phospholamban (PLN) and ryanodine receptor (RYR2) phosphorylation were measured with Western blots. PDE4D −/− hearts had elevated contractility and improved relaxation compared to WT. The PDE4 inhibitor, rolipram (ROL), had no effect on PDE4D−/− hearts but increased contractility in WT hearts to levels observed in PDE4D−/−. Although ICaL did not differ, Ca2+ transient amplitudes and SR Ca2+ content were elevated in PDE4D −/− myocytes compared to WT controls. Ca2+ transients observed in PDE4D−/− myocytes were lowered to WT levels by PKA inhibition with R p-cAMPs while being increased in WT myocytes to PDE4D−/− levels by ROL, suggesting that PDE4D−/− myocytes have increased cAMP levels in SR microdomains. Indeed, phosphorylated PLN (PLN-PO4) was elevated in PDE4D −/− hearts, while ROL enhanced PLN-PO4 in WT to levels observed in knock-out hearts.
Conclusions: PDE4D is the PDE4 isozyme that regulates basal cAMP levels in SR microdomains.
- © 2010 by American Heart Association, Inc.