Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts

Background In murine heart failure models and in humans with diabetic‐related heart hypertrophy, inhibition of phosphodiesterase 5 ( PDE 5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE 5 and β2 adrenergic receptor (β2 AR ), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild‐type and β2 AR 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. PDE 5 selectively associates with β2 AR , but not β1 adrenergic receptor, and inhibition of PDE 5 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 PDE 5 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 β2 AR abolishes sildenafil's effect. Although the PDE 5‐β2 AR association is not altered in HFD , phosphodiesterase 3 displays an increased association with the β2 AR ‐ PDE 5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2 AR ‐ PDE 5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE 5 enhances β2 AR stimulation of cGMP and cAMP signals, as well as protein kinase G–dependent E‐C coupling in HFD myocytes.