Fig. 8Figure 9
Schematic of the proposed mechanism for chronic adrenergic stimulation induced heart failure via cAMP-PKA-PDE4D signaling pathway and protective mechanism of PDE4D inhibition . Sustained adrenergic activation upregulates PDE4D expression via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy. Pharmacological inhibition or knockdown of PDE4D reduced cAMP degradation and activates PKA-CREB-SIRT1 signaling, leading to a restoration of PINK1/Parkin-mediated mitophagy in cardiomyocytes, which may contribute to improvement of cardiac function and hypertrophy.