PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction
PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction
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DOI：
10.1073/pnas.1607728113
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发表时间：
2016-11-08
影响因子：
11.1
通讯作者：
Yan, Chen
中科院分区：
文献类型：
--
作者：
Knight, Walter E.;Chen, Si;Yan, Chen
环核苷酸磷酸二酯酶1C（PDE 1C）代表了人类心肌中的主要磷酸二酯酶活性，但其在心脏中的功能尚不清楚。利用遗传学和药理学方法，我们研究了PDE 1C在心脏重塑和功能障碍发病机制中的表达、调节、功能和潜在机制。PDE 1C表达在小鼠和人类衰竭心脏中上调，并且在心肌细胞中高度表达，但在成纤维细胞中不表达。在成年小鼠心肌细胞中，PDE 1C缺乏或抑制可减轻心肌细胞死亡和凋亡，这在很大程度上依赖于cAMP/PKA和PI 3 K/AKT信号转导。PDE 1C缺乏也以PKA依赖的方式减弱心肌细胞肥大。从PDE 1C缺陷心肌细胞中提取的条件培养基通过涉及心肌细胞和成纤维细胞之间的串扰的机制减弱TGF-β刺激的心脏成纤维细胞活化。在体内，与野生型小鼠相比，PDE 1C基因敲除小鼠中由横向主动脉缩窄诱导的心脏重塑和功能障碍（包括心肌肥大、细胞凋亡、心脏纤维化和收缩功能丧失）显著减弱。这些结果表明，PDE 1C激活在病理性心脏重塑和功能障碍中起着致病作用。鉴于高度特异性PDE 1抑制剂的持续开发和PDE 1C在人类心脏中的高表达水平，我们的发现可能具有相当大的治疗意义。
Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-beta-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.