Table 3.
The roles of individual PDE isoforms in cardiac ischemia injury
| PDE Family | Isoform | Variants | Model in vivo | Model in vitro | Genetic Intervention in vivo | Genetic Intervention in vitro | Inhibitors Used | Positive ↑Negative ↓ | Signaling Pathway | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| PDE2 | Ex vivo perfused mouse heart-reperfusion injury | BAY 60-7550 | ↓ | ↓Arrhythmic events | (271) | |||||
| PDE2A | Ionomycin-NRCM | PDE2A-siRNA | BAY 60-7550 | ↓ | ↑Drp1 phosphorylation ↑mitochondria dynamics | (48) | ||||
| PDE2A3 | LAD ligation mice-MI | PDE2A3-TG | ↓ | ↑Ca2+ homeostasis ↓contractile dysfunction ↓cardiac arrhythmias | (218) | |||||
| PDE3 | ||||||||||
| NRCM per se | Milrinone, cilostamide | ↑ | ↑ICER | (58) | ||||||
| Ischemia-reperfusion dog | Milrinone, olprinone | ↑ | ↑cAMP-PKA-p38 | (318) | ||||||
| Ischemia-reperfusion rat | Olprinone | ↓ | ↑PI3K-Akt ↓ mPTP | (319) | ||||||
| Ex vivo perfused rabbit heart-reperfusion injury | Cilostazol | ↓ | ↑mitoK(Ca) channels | (320) | ||||||
| Ex vivo perfused rabbit heart-reperfusion injury | Milrinone | No effect | (320) | |||||||
| PDE3A | NRCM per se | Adenovirus- antisense-PDE3A | ↑ | ↑ICER | (58) | |||||
| PDE3A1 | Ang II/ISO-NRCM | Adenovirus- PDE3A1 | ↓ | ↑ICER | (58) | |||||
| Ischemia-reperfusion mice | Cardiac-specific overexpression of PDE3A1 | ↓ | ↓ICER | (321) | ||||||
| PDE3B | Ischemia-reperfusion mice | PDE3B−/− mice | ↓ | ↑Ca2+-activated K+ channels, ↓ROS | (59) | |||||
| PDE4 | ||||||||||
| PDE4B | Ischemia-reperfusion mice | PDE4B−/− mice | ↓ | ↑Cardiac microcirculation ↓inflammation | (312) | |||||
| PDE4D | ||||||||||
| PDE4D3 | LAD ligation mice-MI | PDE4D−/− mice | ↑ | ↑RyR2-phosphorylation ↑Ca2+ leakage | (169) | |||||
| PDE5 | Ischemia-reperfusion rabbit | Sildenafil | ↓ | ↑A(1) adenosine receptor activation | (313) | |||||
| Ex vivo perfused mouse heart-reperfusion injury | Sildenafil | ↓ | ↑Mitochondrial K(ATP) channels | (314) |
Boldface indicates that the phosphodiesterase (PDE) plays a negative role in ischemia injury. cAMP, cyclic adenosine monophosphate, Drp1, dynamin-related protein; ICER, Inducible cAMP early repressor; ISO, isoproterenol; LAD, ligation of left anterior coronary artery; MI, myocardial infarction; mPTP, mitochondrial permeability transition pore; NRCM, neonatal rat cardiomyocyte; p38, p38 mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; RyR2, ryanodine receptor 2; TG, transgenic mouse.