Table 2.
The roles of individual PDE isoforms in cardiac hypertrophy
| PDE Family | Isoform | Variants | Expression | Activity | Pathology | Model in vivo | Model in vitro | Genetic Intervention in vivo | Genetic Intervention in vitro | Inhibitors Used | Positive ↑Negative ↓ | Potential Mechanism | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PDE1 | Ang II infusion mice | vinpocetine | ↓ | ↓PDE1 | (281) | ||||||||
| PDE1A | ↑ | ISO infusion mice | Ang II and ISO-NRCM | PDE1A shRNA | IC86340 | ↓ | ↑cGMP-PKG | (23) | |||||
| PDE1C | ↑ | TAC | PDE1C null mice | ↓ | ↑cAMP-PKA | (26) | |||||||
| PDE2 | ↑ | ↑ | Human HF, TAC | (42) | |||||||||
| AAC | Ang II-NRCM | BAY 60-7550 | ↓ | ↑NO-GC-cGMP signaling | (43) | ||||||||
| TAC | NE-NRVM | BAY 60-7550 | ↓ | ↑PKA-NFAT phosphorylation | (278) | ||||||||
| ET-1-NRVM | BAY60-7550 | ↓ | ↓ cAMP-PKA-dependent inhibition of PLCε; ↓cGMP-PKG-dependent inhibition of PLCε | (275) | |||||||||
| PDE2A | Male rats per se | ARVMs per se | PDE2A overexpression rats | ↑ | ↓PKA-mediated NFAT phosphorylation | (278) | |||||||
| PDE2A2 | NE/PE-ARVM | PDE2A2 adenovirus | ↓ | ↓β-Adrenergic responses | (42) | ||||||||
| PDE3 | Human HF | (282, 283) | |||||||||||
| ↓ | TAC | (284) | |||||||||||
| ↑ | ↑ | Salt-induced HF rat | (285) | ||||||||||
| ↑ | TAC | Milrinone | ↓ | ↓p38 MAPK, ↓calcineurin-NFAT | (286) | ||||||||
| NRCMs per se | Cilostamide | ↑ | ↑ PLCε at the Golgi through Epac →↑PI4P hydrolysis | (275) | |||||||||
| NRCMs per se | Cilostamide | ↑ | ↑ PKA not anchored to AKAPs | (278) | |||||||||
| PDE3A | ↓ | ↓ | Human DCM and IHD, TAC | (58) | |||||||||
| PDE3A | ↓ | TAC | (284) | ||||||||||
| PDE3A | TAC | PDE3A-KO | ↓ | (286) | |||||||||
| PDE3A2 | NRCMs per se | Inactive mutants of PDE3A2 | ↑ | ↑cAMP at sites where prohypertrophic effectors | (278) | ||||||||
| PDE3B | TAC | PDE3B-KO | (286) | ||||||||||
| PDE4 | ↑ | ↑ | Salt-induced HF rat | (285) | |||||||||
| ↑ | Human HF with diabetes, HFD mice | Roflumilast | ↓ | ↑cAMP-CREB-Sirt1- SERCA2a- miR-1 | (83) | ||||||||
| NRCMs per se | Rolipram | ↑ | ↑Epac-PLCε at the Golgi →↑PI4P hydrolysis | (275) | |||||||||
| NRCMs per se | Rolipram | ↑ | ↑PKA not anchored to AKAPs | (278) | |||||||||
| ISO-NRCMs | PDE4 activator UCR1C | ↓ | ↓Nuclear PKA -CREB | (287) | |||||||||
| PDE4A | ↓ | TAC | (284) | ||||||||||
| PDE4B | ↓ | TAC | (284) | ||||||||||
| ↓ | Human HF | ISO infusion, TAC | PDE4B-TG mice, AAV9-PDE4B | ↓ | Blunts β-adrenergic response | (288) | |||||||
| PDE4D | TAC | (284) | |||||||||||
| ↑ | Human HF with diabetes, HFD mice | AAV9-PDE4D shRNA | Roflumilast | ↓ | ↑cAMP-CREB-Sirt1-SERCA2a- miR-1 | (83) | |||||||
| PDE4D3 | LIF-NRCM | Rolipram | ↓ | ↓mAKAP-PDE4D3-Epac1-PKAcomplex anchored ERK5 activity | (155) | ||||||||
| NRVMs per se | Inactive mutants of PDE4D3 | ↑ | (278) | ||||||||||
| PDE4D5 | ↑ | Human HF with diabetes, HFD mice | NRVM | PDE4D5 adenovirus | ↑ | ↓cAMP-CREB-Sirt1-SERCA2a- miR-1 | (83) | ||||||
| ISO-NRCM | competitive peptide 58-Pept | ↑ | ↓β-arrestin–PDE4D5 interaction→ ↑ Epac1 recruit to β2AR | (163) | |||||||||
| PDE5 | PDE5A | ↑ | HF (DCM, ICM) | MI | PDE5-TG | ↑ | ↓cGMP | (92) | |||||
| TAC | PDE5-TG | ↑ | ↑Natriuretic peptide-derived cGMP hydrolysis | (289) | |||||||||
| ↑ | CHF, TAC | TAC | Sildenafil | ↓ | ↓Oxidative stress | (290) | |||||||
| TAC | Sildenafil | ↓ | ↑cGMP-↓oxidized PKG1α | (291) | |||||||||
| TAC | Sildenafil | ↓ | Improve T-tubule remodeling | (292) | |||||||||
| PE-NRCM | PDE5A-shRNA | Sildenafil | ↓ | ↑PKG | (91) | ||||||||
| TAC | PE-NRCM | Sildenafil | ↓ | ↓Calcineurin/NFAT, ↓PI3K/Akt, ↓ERK1/2 | (293) | ||||||||
| SHR | Sildenafil | ↓ | ↓Na+/H+ exchanger activity | (294) | |||||||||
| TAC | PE-NRCM | CRD-733 | ↓ | ↑cGMP | (295) | ||||||||
| PDE9 | PDE9A | ↑ | Human (DCM, HFpEF), aortic stenosis, TAC | TAC | PE, ET-1-NRCM | PDE9A-KO | PDE9A-siRNA | PF-9613 | ↓ | ↑natriuretic peptide-cGMP | (123) | ||
| ET-1-NRCM | PF04449613 | ↓ | ↓cGMP-PKG-dependent inhibition of PLCε | (275) | |||||||||
| ISO rat | PE, ISO-NRCM | C33(S) | ↓ | ↑cGMP | (296) |
Boldface indicates that the phosphodiesterase (PDE) plays a negative role in hypertrophy. AAC, abdominal aortic constriction; AAV9, adeno-associated viral vector serotype 9; AKAP, A-kinase anchoring protein; Ang II, angiotensin II; ARVM, adult rat ventricular myocyte; cAMP, cyclic adenosine monophosphate, cGMP, cyclic guanosine monophosphate; CHF, congestive heart failure; CREB, cAMP response element binding protein; DCM, dilated cardiomyopathy; Epac, exchange protein activated by cAMP; ERK, extracellular signal-regulated kinase; ET-1, endothelin-1; GC, guanylyl cyclase; HF, heart failure; HFD, high-fat diet; HFpEF, heart failure with preserved ejection fraction; ICM, ischemic cardiomyopathy; IHD, ischemic heart disease; ISO, isoproterenol; KO, knockout; LIF, leukemia inhibitory factor; miR-1, microRNA-1; NE, norepinephrine; NFAT, Nuclear factor of activated T cells; NO, nitric oxide; NRCM, neonatal rat cardiomyocyte; NRVM, neonatal rat ventricular cardiomyocyte; PE, phenylephrine; PI4P, phosphatidylinositol 4-phosphate; PKA, protein kinase A, PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; SERCA2a, sarco(endo)plasmic reticulum calcium ATPase; SHR, spontaneously hypertensive rat; shRNA, short hairpin RNA; siRNA, short interfering RNA; Sirt1, Sirtuin 1; TAC, transverse aortic constriction; TG, transgenic mice.