title: Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury.
abstract: Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. PDE3 inhibitors are used for acute treatment of congestive heart failure, but are associated with increased incidence of arrhythmias and sudden death with long-term use. We previously reported that chronic PDE3A downregulation or inhibition induced myocyte apoptosis in vitro. However, the cardiac protective effect of PDE3A has not been demonstrated in vivo in disease models. In this study, we examined the role of PDE3A in regulating myocardial function and survival in vivo using genetically engineered transgenic mice with myocardial overexpression of the PDE3A1 isozyme (TG). TG mice have reduced cardiac function characterized by reduced heart rate and ejection fraction (52.5±7.8% vs. 83.9±4.7%) as well as compensatory expansion of left ventricular diameter (4.19±0.19mm vs. 3.10±0.18mm). However, there was no maladaptive increase of fibrosis and apoptosis in TG hearts compared to wild type (WT) hearts, and the survival rates also remained the same. The diminution of cardiac contractile function is very likely attributed to a decrease in beta-adrenergic receptor (β-AR) response in TG mice. Importantly, the myocardial infarct size (4.0±1.8% vs. 24.6±3.8%) and apoptotic cell number (1.3±1.0% vs. 5.6±1.5%) induced by ischemia/reperfusion (I/R) injury were significantly attenuated in TG mice. This was associated with decreased expression of inducible cAMP early repressor (ICER) and increased expression of anti-apoptotic protein BCL-2. To further verify the anti-apoptotic effects of PDE3A1, we performed in vitro apoptosis study in isolated adult TG and WT cardiomyocytes. We found that the apoptotic rates stimulated by hypoxia/reoxygenation or H2O2 were indeed significantly reduced in TG myocytes, and the differences between TG and WT myocytes were completely reversed in the presence of the PDE3 inhibitor milrinone. These together indicate that PDE3A1 negatively regulates β-AR signaling and protects against I/R injury by inhibiting cardiomyocyte apoptosis.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oikawa
authors.forename: Meiping
authors.initials: M
authors.lastname: Wu
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Walter E
authors.initials: WE
authors.lastname: Knight
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cai
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006439:Hemodynamics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism; D009928:Organ Specificity; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011943:Receptors, Adrenergic, beta; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517289:Pde3a protein, mouse
keywords: AAR; B-cell lymphoma 2; BCL-2; CSA; EF; GAPDH; HW; I/R; ICER; ISO; LAD; LV; LV dp/dt max; LV dp/dt min; LVDd; LVDs; LVP; LW; MI; Mil; Myocardial injury; Myocyte apoptosis; Myocyte contractility; PDE3A; PDE3A1; PKA; PLB; Rol; SERCA2; TG; TL; TUNEL; TnC; TnI; Transgenic mice; WT; area at risk; beta-adrenergic receptor; cAMP-dependent protein kinase type A; cross-sectional area; ejection fraction; glyceraldehyde-3-phosphate dehydrogenase; heart weight; inducible cAMP early repressor; ischemia/reperfusion; isoproterenol; left anterior descending; left ventricle; left ventricular diastolic diameter; left ventricular systolic diameter; left ventricular systolic pressure; lung weight; milrinone; myocardial infarction; p-PLB; p-TnI; phosphodiesterase 3A1; phospholamban; phosphorylated TnI; phosphorylated phospholamban; rolipram; sarcoplasmic reticulum calcium ATPase type 2; terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay; the maximum rate of left ventricular pressure decrease; the maximum rate of left ventricular pressure rise; tibia length; transgenic mice; troponin C; troponin I; wild-type mice; β-AR