A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis
A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis
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DOI：
10.1073/pnas.0506489102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Yan, C
中科院分区：
文献类型：
--
作者：
Ding, B;Abe, J;Yan, C
cAMP 在心脏重塑和心力衰竭的进展中起着至关重要的作用。最近，我们发现人类衰竭心脏中 cAMP 水解磷酸二酯酶 3A (PDE3A) 的表达显着降低，同时诱导型 cAMP 早期阻遏蛋白 [ICER] 表达上调。血管紧张素 11 (Ang 11) 和 β-肾上腺素能受体激动剂异丙肾上腺素 (ISO) 也在体外诱导持续的 PDE3A 下调和伴随的 ICER 上调，这在 Ang II 和 ISO 诱导的心肌细胞凋亡中很重要。我们假设PDE3A和ICER之间的相互作用可能构成一个自动调节正反馈环路（PDE3A-ICER反馈环路），并且该环路会导致持续的IPDE3A下调和ICER上调。在这里，我们证明 ICER 诱导抑制了 PDE3A 基因转录。 IPDE3A 下调激活 cAMP/PKA 信号传导，通过 PKA 依赖性稳定 ICER 导致 ICER 上调。对于 Ang 11，PDE3A-ICER 反馈环路的启动取决于 Ang 11 1 型受体 (AT1R)、经典 PKC 和 CREB（cAMP 反应元件结合蛋白）的激活。我们进一步表明 PDE3A-ICER 反馈环路对于 Ang II 诱导的心肌细胞凋亡至关重要。 ISO 和 PDE3 抑制剂还诱导 PDE3A-ICER 反馈环路和随后的心肌细胞凋亡，凸显了 PDE3A-ICER 反馈环路和 cAMP 信号在心肌细胞凋亡中的重要性。我们的研究结果可能提供一种通过抑制 PDE3A-ICER 反馈环路来预防心肌细胞凋亡和心力衰竭进展的治疗范例。
cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor [ICER) expression. Angiotensin 11 (Ang 11) and the beta-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent IPDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. IPDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang 11, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang 11 type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.