Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart.

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

心脏成纤维细胞在高血压和心肌梗死（MI）的作用下被激活并分化为平滑肌样肌成纤维细胞，导致细胞外基质（ECM）重塑、瘢痕形成和心脏功能受损。环腺苷酸（cAMP）和环鸟苷酸（cGMP）依赖性信号通路与心脏成纤维细胞的激活和细胞外基质合成有关。环核苷酸磷酸二酯酶（PDE）活性/表达的失调也与多种疾病相关，目前已有几种PDE抑制剂可用于治疗这些病理状况，或正处于研发阶段。本研究的目的是确定并描述在心脏成纤维细胞激活过程中发生改变且对调节肌成纤维细胞激活和细胞外基质合成具有重要功能的特定PDE同工酶。我们发现，在体外由血管紧张素II（Ang II）和转化生长因子 -β（TGF -β）刺激的活化心脏肌成纤维细胞中，以及在小鼠、大鼠和人类患病心脏的纤维化区域内的体内环境中，Ca²⁺/钙调蛋白刺激的PDE1A同工酶被特异性诱导。通过PDE1选择性抑制剂或PDE1A小干扰RNA（shRNA）抑制PDE1A的功能，可显著降低血管紧张素II或转化生长因子 -β诱导的大鼠心脏成纤维细胞的肌成纤维细胞激活、细胞外基质合成以及促纤维化基因表达。此外，PDE1抑制剂可减轻异丙肾上腺素诱导的小鼠间质纤维化。机制研究表明，PDE1A主要在心脏成纤维细胞的核周和核区域调节独特的cAMP和cGMP池。此外，cAMP - Epac - Rap1和cGMP - PKG信号通路均参与PDE1A介导的胶原蛋白合成调节。这些结果表明，PDE1A的诱导在心脏成纤维细胞激活和心脏纤维化中起关键作用，靶向PDE1A可能会逆转与各种心脏疾病相关的不良心脏重塑。