A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction
A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction
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DOI：
10.1161/circulationaha.119.042178
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发表时间：
2020-01-21
期刊：
影响因子：
37.8
通讯作者：
Yan, Chen
中科院分区：
文献类型：
--
作者：
Chen, Si;Zhang, Yishuai;Yan, Chen
背景：心力衰竭是世界范围内的主要死亡原因。环核苷酸磷酸二酯酶（PDE）通过降解环核苷酸，在心血管生物学和疾病中发挥关键作用。我们的初步筛选研究揭示了PDE 10A在患病心脏中的上调。然而，PDE 10A在心血管生物学和疾病中的作用在很大程度上是未知的。本研究旨在探讨PDE 10A在心肌细胞中的调节和功能，以及在心脏重塑和功能障碍的进展中的作用。方法：我们使用分离的成年小鼠心肌细胞和成纤维细胞，以及临床前肥大和心力衰竭小鼠模型。PDE 10A选择性抑制剂TP-10和PDE 10A基因敲除小鼠的实验结果表明，PDE 10A在正常和运动心肌组织中的表达水平相对较低。然而，PDE 10A在小鼠和人类衰竭心脏中显著上调。在体外，PDE 10A缺乏或用选择性抑制剂TP-10抑制PDE 10A，减弱了由血管紧张素II、苯肾上腺素和异丙肾上腺素诱导的心肌细胞病理性肥大，但不影响由IGF-1（胰岛素样生长因子1）诱导的心肌细胞生理性肥大。TP-10还减少TGF-β（转化生长因子-β）刺激的心脏成纤维细胞活化、增殖、迁移和细胞外基质合成。TP-10处理提高了心肌细胞和心脏成纤维细胞中的cAMP和cGMP水平，与作为cAMP/cGMP双特异性PDE的PDE 10A一致。在体内，整体PDE 10A缺陷显著减弱了通过横向主动脉收缩或通过血管紧张素II输注的慢性神经激素刺激引起的慢性压力超负荷引起的心肌肥大、心脏纤维化和功能障碍。重要的是，我们证明TP-10的药理学作用是通过PDE 10A抑制特异性的。此外，TP-10能够逆转预先建立的心脏肥大和功能障碍。RNA测序和生物信息学分析进一步确定了PDE 10A-regualted转录组参与心脏肥大，纤维化，cardiomyopathy.Conclusions：两者合计，我们的研究阐明了一个新的作用PDE 10A在调节病理性心脏重塑和心力衰竭的发展。鉴于PDE 10A已被证明是一种安全的药物靶点，PDE 10A抑制可能代表了预防和治疗与心脏重塑相关的心脏疾病的新治疗策略。
Background: Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the roles of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction.Methods: We used isolated adult mouse cardiac myocytes and fibroblasts, as well as preclinical mouse models of hypertrophy and heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice were used.Results: We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. In vitro, PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated cardiac myocyte pathological hypertrophy induced by Angiotensin II, phenylephrine, and isoproterenol, but did not affect cardiac myocyte physiological hypertrophy induced by IGF-1 (insulin-like growth factor 1). TP-10 also reduced TGF-beta (transforming growth factor-beta)-stimulated cardiac fibroblast activation, proliferation, migration and extracellular matrix synthesis. TP-10 treatment elevated both cAMP and cGMP levels in cardiac myocytes and cardiac fibroblasts, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. In vivo, global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and dysfunction induced by chronic pressure overload via transverse aorta constriction or chronic neurohormonal stimulation via Angiotensin II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy.Conclusions: Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.