Abstract 9719: Overexpressed Phoshodiesterase 3A1 Protects the Heart against Angiotensin II-induced Cardiac Injury via Regulating Interaction between β-adrenergic and Angiotensin II Signaling Pathways
BACKGROUND: Angiotensin II (AngII) has critical roles in progression of cardiac hypertrophy and fibrosis, leading to subsequent heart failure. Accumulating evidence suggests that there are direct interactions between β-adrenergic and AngII signaling pathways, and β-blocker treatment protects hearts against AngII-induced cardiac injury. Phosphodiesterase 3A (PDE3A) inhibits β-adrenergic receptor (βAR)/protein kinase A (PKA) axis by metabolizing cAMP. Therefore, we hypothesized that overexpressed PDE3A has cardioprotective effects against AngII-induced cardiac injury by regulating AngII signaling.
METHODS AND RESULTS: To induce cardiac injury, AngII (800 ng/kg/min) was continuously infused using osmotic mini-pump for 10 days in wild-type (WT) mice and transgenic (TG) mice with cardiac-specific expression of exogenous PDE3A1. AngII stimulation increased heart weight/body weight ratio by 32% in WT hearts compared with vehicle hearts (5.6±0.5 mg/g vs. 4.3±0.1 mg/g, P<0.05), whereas by 5% in TG hearts (5.8±0.6 mg/g vs. 5.5±0.8 mg/g, ns). Echocardiography revealed that AngII lead to cardiac hypertrophy in WT hearts compared to vehicle hearts (wall thickness, 12.4±1.5 mm vs. 8.2±0.7 mm, P<0.05), but not in TG hearts (10.4±1.5 mm vs. 9.3±0.3 mm, ns). Moreover, AngII-induced cardiac fibrosis was also inhibited in TG hearts compared to WT hearts (4.2±1.1% vs. 6.9±2.6%, P<0.05). Interestingly, basal expression levels of transforming growth factor-β (TGFβ) as well as phosphorylated-phospholamban were inhibited in TG hearts compared to WT hearts, suggesting that overexpressed PDE3A regulated AngII/TGFβ and βAR/PKA axis.
CONCLUSIONS: We thus conclude that PDE3A inhibits AngII-induced cardiac hypertrophy and fibrosis via regulating the interaction between β-AR/PKA and AngII/TGFβ axis.
- © 2012 by American Heart Association, Inc.