Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

Figures

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  Figure 1. Simplified scheme of phosphodiesterase (PDE)-mediated cGMP/cAMP crosstalk. cAMP generated by adenylate cyclase (AC) upon stimulation of β-adrenergic receptors leads to the activation of protein kinase A (PKA) and the family of exchange proteins directly activated by cAMP (EPAC). cGMP generated either by NO-sensitive soluble guanylyl cyclase (sGC) or natriuretic peptide (NP)-sensitive GC-receptors leads to the stimulation of cGMP-dependent protein kinase G (PKG). In diverse subcellular compartments, cGMP stimulates phosphodiesterase 2 (PDE2) but competitively inhibits PDE3-mediated cAMP hydrolysis. PDE5 and PDE9 degrade cGMP in cardiomyocytes. Figure was produced using Servier Medical Art (Available online: http://smart.servier.com).

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  Figure 2. PDE2-mediated cGMP/cAMP crosstalk mechanisms in cardiomyocytes. PDE2 regulates cAMP levels downstream of β-AR signalling at a compartmentalized level, modulating PKA- and potentially EPAC/CaMKII-mediated activation of numerous targets. First, PDE2 regulatory activities are detected at the plasmalemma, modulating ICa,L and possibly HCN If currents. Additionally, PDE2 regulates components of the ECC machinery at the SR (RyR2 and PLB) and sarcomeres (TnT1 and MyBP-C). PDE2 transcriptional regulatory effects are also reported in the nuclear compartment in addition to its role to regulate mitochondrial function and dynamics. PDE2 is also activated by cGMP synthesized downstream of both sGC and pGC, to promote a negative cGMP/cAMP crosstalk mechanisms in the aforementioned compartments. (PDE2 inhibition (PDE2i)) Figure was produced using Servier Medical Art (Available online: http://smart.servier.com).

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  Figure 3. Schematic illustration of the PDE2-mediated cGMP/cAMP crosstalk in cardiac fibroblasts. PDE2 overexpression or enhanced activity subsequent to iNOS/NO/cGMP stimulation accelerates cAMP hydrolysis in cardiac fibroblasts. Diminished cAMP levels prompt fibroblast activation and differentiation into myofibroblasts promoting α-smooth muscle actin (αSMA), connective tissue growth factor (CTGF) and collagen disposition, increasing muscle stiffness. Figure was produced using Servier Medical Art (Available online: http://smart.servier.com).

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  Figure 4. Schematic illustration of the PDE2-mediated cGMP/cAMP crosstalk in endothelial cells. PDE2 stimulates endothelial cell proliferation and angiogenesis by hydrolyzing cAMP (which reduces cell proliferation) and stimulating ROS production through Rac1 and NADPH oxidases, inducing cell proliferation and angiogenesis together with VEGF. TNF-α promotes BNP, increasing cGMP level; consequently, cGMP activates PDE2 cAMP and cGMP hydrolyzing activity and PDE2 also stimulates thrombin. This results in enhanced neutrophil infiltration, increasing inflammation. Figure was produced using Servier Medical Art (Available online: http://smart.servier.com).