Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction
Phosphodiesterase 2 Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction
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DOI：
10.1161/circresaha.116.310069
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发表时间：
2017-01-06
影响因子：
20.1
通讯作者：
El-Armouche, Ali
中科院分区：
文献类型：
--
作者：
Vettel, Christiane;Lindner, Marta;El-Armouche, Ali
理由：磷酸二酯酶2是一种双底物酯酶，具有受cGMP刺激的独特性质，但主要水解cAMP。心肌磷酸二酯酶2在人类心力衰竭中上调，但其在心脏中的作用尚不清楚。目的：探讨磷酸二酯酶2在心功能、心律失常倾向和心肌梗死中的作用。方法与结果：药理抑制磷酸二酯酶2 （BAY 60-7550， BAY）对健康小鼠最大β -肾上腺素能受体激活有显著的正向变时作用。在慢性儿茶酚胺诱导的病理条件下，BAY可逆转β -肾上腺素受体介导的弱肌力和慢性。相反，心脏特异性磷酸二酯酶2转基因（TG）小鼠的心电图遥测显示静息和最大心率明显降低，而心输出量由于心脏收缩更大而完全保留。这种耐受性良好的表型在老年TG中持续存在，没有心脏病理或过早死亡的迹象。在儿茶酚胺注射诱发心律失常期间，TG动物对诱发性室性心律失常具有抵抗性。因此，在分离的TG心肌细胞中进行的Ca2+火花分析显示，Ca2+泄漏显著减少，Ca2+循环蛋白（包括ryanodine受体2型）的基础磷酸化水平降低。此外，TG还能改善心肌梗死后的心功能。结论：内源性磷酸二酯酶2参与心率调节。较高的磷酸二酯酶2丰度可预防心律失常并改善严重缺血损伤后的收缩力。因此，激活心肌磷酸二酯酶2可能是一种新的细胞内抗肾上腺素能治疗策略，可以保护心脏免受心律失常和收缩功能障碍的影响。
Rationale: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.Objective: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.Methods and Results: Pharmacological inhibition of phosphodiesterase 2 (BAY 60-7550, BAY) led to a significant positive chronotropic effect on top of maximal beta-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated beta-adrenoceptor-mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.Conclusions: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction.