Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.

BACKGROUND AND PURPOSE: Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) is impaired in heart failure. Phosphodiesterases (PDEs) are implicated in the modulation of local cAMP signals and protein kinase A (PKA) activity essential for cardiac function. We characterise PDE isoforms that underlie decreased activities of SERCA2a and reduced cardiac contractile function in diabetic cardiomyopathy. EXPERIMENTAL APPROACH: Wild type mice were fed with either normal chow or a high-fat diet (HFD). Cardiomyocytes were isolated for excitation-contraction coupling (ECC), fluorescence resonant energy transfer PKA biosensor and proximity ligation assays. KEY RESULTS: The upregulated PDE4D3 and PDE4D9 isoforms in HFD cardiomyocytes specifically bound to SERCA2a but not ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum (SR). The increased association of PDE4D isoforms with SERCA2a in HFD cardiomyocytes led to reduced local PKA activities and phosphorylation of phospholamban (PLB) but minimally effected the PKA activities and phosphorylation of RyR2. These changes correlate with slower calcium decay tau in the SR and attenuation of ECC in HFD cardiomyocytes. Selective inhibition of PDE4D3 or PDE4D9 restored PKA activities and phosphorylation of PLB at the SERCA2a complex, recovered calcium decay tau, and increased ECC in HFD cardiomyocytes. Therapies with PDE4 inhibitor roflumilast, PDE4D inhibitor BPN14770 or genetical deletion of PDE4D restored PKA phosphorylation of PLB and cardiac contractile function. CONCLUSION AND IMPLICATIONS: The current study identifies upregulation of specific PDE4D isoforms that selectively inhibit SERCA2a function in HFD-induced cardiomyopathy, indicating that this remodelling can be targeted to restore cardiac contractility in diabetic cardiomyopathy.