Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals.
Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals.
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心脏肥大中营地磷酸二酯酶的表达和活性下降及其对β-肾上腺素能cAMP信号的影响。
DOI：
10.1161/circresaha.109.197947
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发表时间：
2009-10-09
影响因子：
20.1
通讯作者：
Vandecasteele G
中科院分区：
文献类型：
--
作者：
Abi-Gerges A;Richter W;Lefebvre F;Mateo P;Varin A;Heymes C;Samuel JL;Lugnier C;Conti M;Fischmeister R;Vandecasteele G
多环核苷酸磷酸二酯酶（PDE）降解心肌细胞中的cAMP，但PDE在病理性心脏肥大（CH）过程中控制cAMP信号转导的作用尚不清楚。评估心脏收缩力的β-肾上腺素能调节并表征CH后心肌细胞cAMP信号和cAMP-PDE表达和活性的变化。通过胸主动脉结扎在大鼠中诱导CH 5周的时间段，并通过解剖测量和超声心动图证实。在Langendorff灌注心脏中评价离体心肌功能。在单个心肌细胞中表达工程化的环核苷酸门控通道（CNG），以使用相关CNG电流（ICNG）的全细胞膜片钳记录来监测肌膜下cAMP。在纯化的心肌细胞中测定PDE变体活性和蛋白水平。与假手术组相比，主动脉瓣狭窄组大鼠心脏重量增加了67%。在离体肥大心脏中，对最大β肾上腺素能刺激的正性肌力反应降低了54%，同时肥大心肌细胞中肌膜下cAMP水平降低了沿着32%。由于PDE 3A、PDE 4A和PDE 4 B减少，而PDE 4D不变，肥大肌细胞中总cAMP水解活性以及PDE 3和PDE 4活性降低。在肥大的心肌细胞中，PDE对β-肾上腺素能cAMP信号的调节减弱，如IBMX（100 μmol/L）以及PDE 3抑制剂西洛酰胺（1 μmol/L）和PDE 4抑制剂Ro 201724（10 μmol/L）的减弱作用所示。β-肾上腺素能脱敏伴随着CH中cAMP-PDE的减少和β-肾上腺素能cAMP信号调节的改变。
Multiple cyclic nucleotide phosphodiesterases (PDEs) degrade cAMP in cardiomyocytes but the role of PDEs in controlling cAMP signaling during pathological cardiac hypertrophy (CH) is poorly defined. Evaluate the β-adrenergic regulation of cardiac contractility and characterize the changes in cardiomyocyte cAMP signals and cAMP-PDE expression and activity following CH. CH was induced in rats by thoracic aortic banding over a time period of 5 weeks and was confirmed by anatomical measurements and echocardiography. Ex vivo myocardial function was evaluated in Langendorff perfused hearts. Engineered cyclic nucleotide-gated channels (CNG) were expressed in single cardiomyocytes to monitor subsarcolemmal cAMP using whole-cell patch-clamp recordings of the associated CNG current (ICNG). PDE variant activity and protein level were determined in purified cardiomyocytes. Aortic stenosis rats exhibited a 67% increase in heart weight compared to sham-operated animals. The inotropic response to maximal β-adrenergic stimulation was reduced by ∼54% in isolated hypertrophied hearts, along with a ∼32% decrease in subsarcolemmal cAMP levels in hypertrophied myocytes. Total cAMP hydrolytic activity as well as PDE3 and PDE4 activities were reduced in hypertrophied myocytes, due to a diminution of PDE3A, PDE4A and PDE4B whereas PDE4D was unchanged. Regulation of β-adrenergic cAMP signals by PDEs was blunted in hypertrophied myocytes, as demonstrated by the diminished effects of IBMX (100 μmol/L) and of both the PDE3 inhibitor cilostamide (1 μmol/L) and the PDE4 inhibitor Ro 201724 (10 μmol/L). β-adrenergic desensitization is accompanied by a reduction in cAMP-PDE and an altered modulation of β-adrenergic cAMP signals in CH.