Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current.
Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current.
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DOI：
10.1161/circresaha.111.250464
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发表时间：
2011-10-14
影响因子：
20.1
通讯作者：
Backx PH
中科院分区：
文献类型：
--
作者：
Beca S;Helli PB;Simpson JA;Zhao D;Farman GP;Jones P;Tian X;Wilson LS;Ahmad F;Chen SRW;Movsesian MA;Manganiello V;Maurice DH;Conti M;Backx PH
Baseline contractility of mouse hearts is modulated in a PI3Kγ-dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticular (SR) calcium-ATPase (SERCA2a). To determine whether PDE4D regulates basal cAMP levels, phospholamban (PLN) phosphorylation and SERCA2a activity in SR microdomains. We assessed myocardial function in PDE4D-deficient (PDE4D−/−) and littermate wild-type (WT) mice at 10-12 weeks of age. Baseline cardiac contractility in PDE4D−/− mice was elevated in vivo and in Langendorff perfused hearts, while isolated PDE4D−/− cardiomyocytes showed increased Ca2+ transient amplitudes and SR Ca2+content, but unchanged ICa(L), compared to WT. The PKA inhibitor, Rp-cAMPS, lowered Ca2+ transient amplitudes and SR Ca2+ content in PDE4D−/− cardiomyocytes to WT levels. The PDE4 inhibitor rolipram (ROL) had no effect on cardiac contractility, Ca2+ transients or SR Ca2+ content in PDE4D−/− preparations but increased these parameters in WT hearts to levels indistinguishable from those in PDE4D−/−. The functional changes in PDE4D−/− myocardium were associated with increased PLN phosphorylation (pPLN) but not RyR2 receptor phosphorylation. ROL increased pPLN in WT cardiomyocytes to levels indistinguishable from those in PDE4D−/− cardiomyocytes. In murine and failing human hearts, PDE4D co-immunoprecipitated with SERCA2a but not with RyR2. PDE4D regulates basal cAMP levels in SR microdomains through its interactions with SERCA2a-PLN. Since Ca2+ transient amplitudes are reduced in failing human myocardium, these observations may have therapeutic implications for patients with heart failure.
