Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA.
Int J Mol Sci. 2018 Nov 22;19(12):3704. doi: 10.3390/ijms19123704.
Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARα), leads to elevated cardiac mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either or cardiomyocyte-specific , the major subunit of Mediator complex, we show that Wy-14,643-mediated induction fails to occur in the absence of and in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARα binds to the upstream promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac is a direct transcriptional target of PPARα and that may be required for the PPARα mediated transcriptional activation of cardiac .
磷酸二酯酶 1C（PDE1C）在哺乳动物心脏中表达，通过控制第二信使环 AMP 和环 GMP（分别为 cAMP 和 cGMP）的水平来调节心脏功能。然而，心脏调节的分子机制目前尚不清楚。在这项研究中，我们证明了 Wy-14,643（核受体过氧化物酶体增殖物激活受体α（PPARα）的有效配体）处理野生型小鼠和 H9c2 成肌细胞可导致心脏 PDE1C mRNA 和蛋白水平升高，这与 cAMP 水平降低有关。此外，使用缺乏 Mediator 复合物主要亚基 或心肌细胞特异性 的小鼠，我们表明 Wy-14,643 介导的 诱导在心脏中缺乏 和 时不会发生。最后，通过染色质免疫沉淀测定，我们证明 PPARα 结合到两个位点的上游 启动子序列上，其中一个是具有强结合能力的回文序列（agcTAGGttatcttaacctagc）。基于这些观察结果，我们得出结论，心脏 是 PPARα 的直接转录靶标，并且 可能是 PPARα 介导的心脏 转录激活所必需的。
