Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming
Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming
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DOI：
10.1038/s41467-019-08626-y
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发表时间：
2019-02-20
影响因子：
16.6
通讯作者：
Ieda, Masaki
中科院分区：
文献类型：
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作者：
Muraoka, Naoto;Nara, Kaori;Ieda, Masaki
从成纤维细胞直接心脏重编程可能是一种有前途的方法，用于儿童和成人患者的疾病建模，药物筛选和心脏再生。然而，与胚胎成纤维细胞相比，出生后和成年成纤维细胞的重编程效率较低，与衰老相关的心脏重编程障碍仍未确定。在这项研究中，我们筛选了8400种化合物，发现双氯芬酸钠（双氯芬酸），一种非甾体抗炎药，与Gata 4、Mef 2c和Tbx 5（GMT）或GMT加Hand 2联合使用，大大增强了心脏重编程。有趣的是，双氯芬酸促进了小鼠出生后和成年尾尖成纤维细胞（TTF）的心脏重编程，但在小鼠胚胎成纤维细胞（MEF）中没有。从机制上讲，双氯芬酸通过抑制环氧合酶-2、前列腺素E2/前列腺素E受体4、环AMP/蛋白激酶A和白细胞介素1 β信号传导以及通过沉默出生后和成年TTF中激活的炎症和成纤维细胞程序来增强心脏重编程。因此，抗炎代表了与衰老相关的心脏重编程的新靶点。
Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1 beta signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation represents a new target for cardiac reprogramming associated with aging.