PDE3A Regulates Basal Myocardial Contractility Through Interacting with SERCA2a-Signaling Complexes in Mouse Heart
Rationale: cAMP is an important regulator of myocardial function, and regulation of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) is a critical determinant of the amplitude, duration, and compartmentation of cAMP-mediated signaling. The role of different PDE isozymes, particularly PDE3A versus PDE3B, in the regulation of heart function remains unclear.
Objective: To determine the relative contribution of PDE3A versus PDE3B isozymes in the regulation of heart function and to dissect the molecular basis for this regulation.
Methods and Results: Compared to wild-type (WT) littermates, cardiac contractility and relaxation were enhanced in isolated hearts from PDE3A-/-, but not PDE3B-/-, mice. Furthermore, PDE3 inhibition had no effect on PDE3A-/- hearts but increased contractility in WT (as expected) and PDE3B-/- hearts to levels indistinguishable from PDE3A-/-. The enhanced contractility in PDE3A-/- hearts was associated with cAMP-dependent elevations in Ca2+ transient amplitudes and increased SR Ca2+ content, without changes in L-type Ca2+ currents (ICaL) of cardiomyocytes, as well as with increased SR Ca2+-ATPase (SERCA2a) activity, SR Ca2+ uptake rates, and phospholamban (PLN) phosphorylation in SR fractions. Consistent with these observations, PDE3 activity was reduced ~8-fold in SR fractions from PDE3A-/- hearts. Co-immunoprecipitation experiments further revealed that PDE3A associates with both SERCA2a and PLN in a complex which also contains AKAP-18, PKA-RII and PP2A.
Conclusions: Our data support the conclusion that PDE3A is the primary PDE3 isozyme modulating basal contractility and SR Ca2+ content by regulating cAMP in microdomains containing macromolecular complexes of SERCA2a-PLN-PDE3A.
- Received September 11, 2012.
- Revision received November 2, 2012.
- Accepted November 19, 2012.
- Copyright © 2012, Circulation Research