Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany.
Klinik für Innere Medizin und Kardiologie, Dresden Heart Center, Dresden University of Technology, 01307 Dresden, Germany.
Int J Mol Sci. 2021 May 1;22(9):4816. doi: 10.3390/ijms22094816.
Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias.
Cellular arrhythmia, ion currents, and Ca-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates.
Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I and Ca-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in perfused WT hearts after reperfusion injury.
Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.
磷酸二酯酶（PDE）对心肌 cAMP 和 cGMP 水平的调节至关重要。PDE2 被 cGMP 刺激以水解 cAMP，介导两条途径之间的负性串扰。心力衰竭中 PDE2 的上调导致对β-肾上腺素能过度刺激的脱敏。在异丙肾上腺素（ISO）注射后，PDE2 过表达小鼠（PDE2 OE）对心室性心律失常有保护作用。在这里，我们研究了 PDE2 OE 对心律失常易感性影响的机制。
在 PDE2 OE 和 WT 同窝仔鼠的心室肌细胞中评估细胞性心律失常、离子电流和 Ca 火花。
在基础条件下，PDE2 OE 和 WT 的动作电位（AP）形态相似。ISO 刺激显著增加了 WT 中的后去极化和自发性 AP 的发生率，而在 PDE2 OE 中则明显减少。在 WT 中观察到的 ISO 诱导的 I 增加在 PDE2 OE 中被阻止。此外，ISO 诱导的、Epac 和 CaMKII 依赖性的 I 和 Ca 火花频率的增加在 PDE2 OE 中减弱，而直接 Epac 激活的作用在两组中相似。最后，PDE2 抑制促进了再灌注损伤后灌注 WT 心脏中的心律失常事件。
较高的 PDE2 丰度通过防止 Epac 和 CaMKII 介导的细胞触发增加来保护 ISO 诱导的心脏性心律失常。因此，激活心肌 PDE2 可能是 HF 中一种新的细胞内抗心律失常治疗策略。
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