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Background In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.
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