Phosphodiesterase Type 3A Regulates Basal Myocardial Contractility Through Interacting With Sarcoplasmic Reticulum Calcium ATPase Type 2a Signaling Complexes in Mouse Heart

被引：116

作者：

Beca, Sanja ^{[3
]}

Ahmad, Faiyaz

Shen, Weixing

Liu, Jie ^{[3
]}

Makary, Samy ^{[3
,5
]}

Polidovitch, Nazari ^{[3
]}

Sun, Junhui ^{[2
]}

Hockman, Steven

Chung, Youn Wook

Movsesian, Matthew ^{[6
]}

Murphy, Elizabeth ^{[2
]}

Manganiello, Vincent ^{[1
]}

Backx, Peter H. ^{[3
,4
,5
]}

机构：

[1] NHLBI, Lab Biochem Physiol, CPB, NIH, Bethesda, MD 20892 USA

[2] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA

[3] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada

[5] Univ Hlth Network, Div Cardiol, Toronto, ON, Canada

[6] VA Salt Lake City Hlth Care Syst, Cardiol Sect, Salt Lake City, UT USA

来源：

CIRCULATION RESEARCH | 2013年 / 112卷 / 02期

基金：

加拿大健康研究院;

关键词：

cAMP; calcium regulation; contractility; phosphodiesterase type 3A knock-out mice; sarcoplasmic reticulum calcium ATPase type 2a; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; CAMP EARLY REPRESSOR; CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; ADRENERGIC-RECEPTOR; GENE-EXPRESSION; CA2+ UPTAKE; CROSS-TALK; FAILURE; MICE;

D O I：

10.1161/CIRCRESAHA.111.300003

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.)

引用

页码：289 / +

页数：27

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