Journal
CIRCULATION RESEARCH
Volume 112, Issue 2, Pages 289-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.300003
Keywords
cAMP; calcium regulation; contractility; phosphodiesterase type 3A knock-out mice; sarcoplasmic reticulum calcium ATPase type 2a
Funding
- Canadian Institutes of Health Research [MOP-62954]
- National Heart, Lung, and Blood Institute (NHLBI)
- US Department of Veterans Affairs
- American Heart Association
- Foundation Leducq (Transatlantic Network of Excellence) [06CVD 02]
- Heart and Stroke Richard Lewar Center of Excellence, University of Toronto
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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 vs PDE3B, in the regulation of heart function remains unclear. Objective: To determine the relative contribution of PDE3A vs PDE3B isozymes in the regulation of heart function and to dissect the molecular basis for this regulation. Methods and Results: Compared with wild-type 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 wild-type (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 sarcoplasmic reticulum (SR) Ca2+ content, without changes in L-type Ca2+ currents of cardiomyocytes, as well as with increased SR Ca2+-ATPase type 2a activity, SR Ca2+ uptake rates, and phospholamban phosphorylation in SR fractions. Consistent with these observations, PDE3 activity was reduced approximate to 8-fold in SR fractions from PDE3A(-/-) hearts. Coimmunoprecipitation experiments further revealed that PDE3A associates with both SR calcium ATPase type 2a and phospholamban in a complex that also contains A-kinase anchoring protein-18, protein kinase type A-RII, and protein phosphatase type 2A. 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 SR calcium ATPase type 2a-phospholamban-PDE3A. (Circ Res. 2013;112:289-297.)
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