Phosphodiesterase in heart and vessels: from physiology to diseases

Figures

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  FIGURE 1.. Classification and specificity of phosphodiesterases (PDEs) toward cyclic nucleotides and downstream effectors. PDE4, 7, and 8 hydrolyze cAMP, whereas PDE5, 6, and 9 hydrolyze cGMP. The other PDEs, including PDE1, 2, 3, 10, and 11, hydrolyze both cAMP and cGMP. cAMP targets protein kinase A (PKA), exchange protein directly activated by cAMP (Epac), hyperpolarization-activated cyclic nucleotide-gated channel (HCN), and popeye domain containing protein (POPDC), whereas cGMP targets protein kinase G (PKG), cyclic nucleotide-gated channel (CNG), and PDE.

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  FIGURE 2.. Structure and regulation of phosphodiesterases (PDEs). The catalytic domains conserved in the carboxy terminal of PDEs are depicted as blue cylinders. These enzymes can be precisely regulated by specific targeting domains and modifications, such as phosphorylation, which enables subcellular localization and activity of PDEs. Certain PDEs can dimerize; long isoforms of PDE4, for example, dimerize because of the presence of 2 upstream conserved regions (UCR1 and UCR2). Other PDEs such as PDE2 and PDE5 form a dimer by means of their GAF [cyclic guanylate monophosphate (cGMP)-dependent phosphodiesterase, Anabaena adenylyl cyclase, Escherichia coli FhlA] domains. PDEs with GAF domains, such as PDE2, PDE5, PDE10A and PDE11, are regulated by cyclic nucleotides, with cGMP activating PDE2 and cAMP inhibiting PDE10. The structure of PDE5A with tadalafil is shown at bottom right. CaM, calmodulin; CaMKII, Ca2+/CaM-dependent kinase II; ERK, extracellular signaling-related kinase; PAS, Per-Arnt-Sim; PKA, protein kinase A; PKB, protein kinase B; TM, transmembrane domain.

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  FIGURE 3.. Subcellular localization of phosphodiesterase (PDE) signalosomes in cardiomyocytes. PDEs form signalosomes with various protein partners, such as protein kinase A (PKA), PKA anchoring proteins, and receptors, which are localized in distinct subcellular compartments of cardiomyocytes. AKAP, A-kinase anchoring protein; β1AR, β1 adrenergic receptor; β2AR, β2 adrenergic receptor; Cav3, caveolin 3; Epac, exchange protein activated by cAMP; ERK, extracellular signaling-related kinase; IK, calcium-activated potassium channel; LTCC, L-type calcium channel; NCX, sodium/calcium exchanger; PKG, protein kinase G; PLB, phospholamban; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; RyR2, ryanodine receptor 2; SERCA, sarco(endo)plasmic reticulum calcium ATPase.

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  FIGURE 4.. The expression and function of phosphodiesterases (PDEs) in the cardiovascular system. The cartoon highlights the expression of individual isoforms in different cardiovascular cells. The colors indicate the positive, negative, or bidirectional roles of PDE isoforms in specific function in the heart and vessels. VSMC, vascular smooth muscle cell.

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  FIGURE 5.. Schematic illustration of phosphodiesterases (PDEs) in cardiac excitation-contraction coupling. A2R, adenosine receptor 2, AC, adenylyl cyclase; ANP, atrial natriuretic peptide; AKAP, A-kinase anchoring protein; β-AR, β adrenergic receptor; cAMP, cyclic adenosine monophosphate, cGMP, cyclic guanosine monophosphate; Gi, inhibitor G protein; Gs, stimulatory G protein; LTCC, L-type calcium channel; NPR2, natriuretic peptide receptor 2; PKA, protein kinase A; PKG, protein kinase G; PLB, phospholamban; PP2A, protein phosphatase 2A; RyR2, ryanodine receptor 2; SERCA, sarco(endo)plasmic reticulum calcium ATPase; sGC, soluble guanylyl cyclase; TnI, troponin I.

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  FIGURE 6.. Schematic illustration of phosphodiesterases (PDEs) in the regulation of heart rate and arrhythmia. AC, adenylyl cyclase; AKAP, A-kinase anchoring protein; β1AR, β1 adrenergic receptor; β2AR, β2 adrenergic receptor; β-arr, β-arrestin; CaMKII, Ca2+/calmodulin-dependent kinase II; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; Epac, exchange protein activated by cAMP; Gi, inhibitor G protein; Gs, stimulatory G protein; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; LTCC, L-type calcium channel; Na/K-ATPase, sodium-potassium-ATPase; NOS, nitric oxide synthase; P, phosphate; PKA, protein kinase A; PLB, phospholamban; POPDC, popeye domain containing protein; RyR2, ryanodine receptor 2; SERCA, sarco(endo)plasmic reticulum calcium ATPase; sGC, soluble guanylyl cyclase.

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  FIGURE 7.. Schematic illustration of phosphodiesterases (PDEs) in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in cardiac hypertrophy. The cartoon highlights the subcellular regulation of cAMP and cGMP induced by different neurohormonal stimuli in driving cardiac hypertrophy. AC, adenylyl cyclase; AngII, angiotensin II; AKAP, A-kinase anchoring protein; βAR, β adrenergic receptor; β-arr, β-arrestin; CaMKII, Ca2+/calmodulin-dependent kinase II; CNP, C-type natriuretic peptide; DAG, diacylglycerol; Epac, exchange protein activated by cAMP; ET-1, endothelin-1, Gαq, Gαq protein; Gβγ, Gβ and Gγ protein; Gi, inhibitor G protein; GPCR, G protein-coupled receptor; Gs, stimulatory G protein; HDAC, histone deacetylase; IP2, inositol-4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate receptor; MAPK, mitogen-activated protein kinase; MEF2, myocyte enhancing factor 2; miR-1, microRNA-1; NFAT, Nuclear factor of activated T cells; NPR2, natriuretic peptide receptor 2; NOS, nitric oxide synthase; PE, phenylephrine; PI4P, phosphatidylinositol-4-phosphate; PKA, protein kinase A, PKC, protein kinase C; PLC, phospholipase…

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  FIGURE 8.. Schematic illustration of the expression and function of phosphodiesterases (PDEs) in the arterial vessel and their involvement in vascular diseases. AAA, abdominal aortic aneurysm; EC, endothelial cell; PAH, pulmonary arterial hypertension; SMC, smooth muscle cell.

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  FIGURE 9.. Schematic illustration of phosphodiesterases (PDEs) in smooth muscle cells. The cartoon highlights the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by PDEs in smooth muscle cells to control vessel constriction and proliferation. CaM, calmodulin; GPCR, G protein-coupled receptor; NO, nitric oxide; NP, natriuretic peptide; sGC, soluble guanylyl cyclase.

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  FIGURE 10.. Schematic illustration of phosphodiesterases (PDEs) in endothelial cells. The cartoon highlights the roles of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and various PDEs (PDE2, 3, and 4) in regulating endothelial cell permeability. ANP, atrial natriuretic peptide; Epac, exchange protein activated by cAMP; NO, nitric oxide; PKA, protein kinase A, TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.

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  FIGURE 11.. Clinical phosphodiesterase (PDE) inhibitors in cardiovascular diseases.