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-β (transforming growth factor-β)-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.

中文翻译：

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环核苷酸磷酸二酯酶 10A 在病理性心脏重构和功能障碍中的新作用。

背景心力衰竭是全世界死亡的主要原因。环核苷酸磷酸二酯酶 (PDE) 通过环核苷酸的降解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患病心脏中 PDE10A 的上调。然而，PDE10A 在心血管生物学和疾病中的作用在很大程度上是未知的。目前的研究旨在研究 PDE10A 在心脏细胞中以及在心脏重塑和功能障碍进展中的调节和功能。方法我们使用分离的成年小鼠心肌细胞和成纤维细胞，以及肥大和心力衰竭的临床前小鼠模型。使用了 PDE10A 选择性抑制剂 TP-10 和全球 PDE10A 敲除小鼠。结果 我们发现 PDE10A 表达在正常和运动心脏组织中仍然相对较低。然而，PDE10A 在小鼠和人类衰竭的心脏中显着上调。在体外，PDE10A 缺乏或用选择性抑制剂 TP-10 抑制 PDE10A，减弱了血管紧张素 II、去氧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 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 还减少了 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 PDE10A 一致。体内，整体 PDE10A 缺乏显着减轻了由横主动脉收缩引起的慢性压力超负荷或血管紧张素 II 输注引起的慢性神经激素刺激引起的心肌肥大、心脏纤维化和功能障碍。重要的是，我们证明了 TP-10 的药理作用是通过 PDE10A 抑制来实现的。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 PDE10A 调节的转录组，与心脏肥大、纤维化和心肌病有关。结论 总之，我们的研究阐明了 PDE10A 在调节病理性心脏重塑和心力衰竭发展中的新作用。鉴于 PDE10A 已被证明是一个安全的药物靶点，