Induction of Senescence by Loss of Gata4 in Cardiac Fibroblasts.
Induction of Senescence by Loss of Gata4 in Cardiac Fibroblasts.
复制标题
DOI：
10.3390/cells12121652
复制
发表时间：
2023-06-17
期刊：
影响因子：
6
通讯作者：
Zhu, Hua
中科院分区：
文献类型：
--
作者：
Zhang, Zhentao;Shayani, Gabriella;Xu, Yanping;Kim, Ashley;Hong, Yurim;Feng, Haiyue;Zhu, Hua
心脏成纤维细胞是各种心脏疾病心脏修复过程中心脏纤维化的主要来源。虽然已经表明心脏成纤维细胞响应于心脏损伤而衰老，但尚不清楚心脏成纤维细胞的衰老是如何在体内调节的。Gata 4是心脏发育所必需的心源性转录因子，也在心脏成纤维细胞中表达。然而，Gata 4在心脏成纤维细胞中的作用仍然难以捉摸。为了确定Gata 4在心脏成纤维细胞中的作用，我们通过将Tcf 21-MerCreMer小鼠与Gata 4fl/fl小鼠杂交来产生心脏成纤维细胞特异性Gata 4敲除小鼠。使用这种小鼠模型，我们可以在他莫昔芬给药后以诱导方式在Tcf 21阳性心脏成纤维细胞中遗传消融Gata 4。我们发现心脏成纤维细胞特异性缺失Gata 4在体内和体外自发诱导心脏成纤维细胞衰老。我们还发现，Gata 4在心肌细胞和非心肌细胞中的表达在老年心脏中显著降低。有趣的是，当αMHC-MerCreMer小鼠与Gata 4fl/fl小鼠繁殖以产生心肌细胞特异性Gata 4敲除小鼠时，在心脏中未检测到衰老细胞。综上所述，我们的研究结果表明，心脏成纤维细胞中Gata 4缺陷激活了细胞衰老的程序，这表明心脏成纤维细胞衰老的一种新的分子机制。
Cardiac fibroblasts are a major source of cardiac fibrosis during heart repair processes in various heart diseases. Although it has been shown that cardiac fibroblasts become senescent in response to heart injury, it is unknown how the senescence of cardiac fibroblasts is regulated in vivo. Gata4, a cardiogenic transcription factor essential for heart development, is also expressed in cardiac fibroblasts. However, it remains elusive about the role of Gata4 in cardiac fibroblasts. To define the role of Gata4 in cardiac fibroblasts, we generated cardiac fibroblast-specific Gata4 knockout mice by cross-breeding Tcf21-MerCreMer mice with Gata4fl/fl mice. Using this mouse model, we could genetically ablate Gata4 in Tcf21 positive cardiac fibroblasts in an inducible manner upon tamoxifen administration. We found that cardiac fibroblast-specific deletion of Gata4 spontaneously induces senescence in cardiac fibroblasts in vivo and in vitro. We also found that Gata4 expression in both cardiomyocytes and non-myocytes significantly decreases in the aged heart. Interestingly, when αMHC-MerCreMer mice were bred with Gata4fl/fl mice to generate cardiomyocyte-specific Gata4 knockout mice, no senescent cells were detected in the hearts. Taken together, our results demonstrate that Gata4 deficiency in cardiac fibroblasts activates a program of cellular senescence, suggesting a novel molecular mechanism of cardiac fibroblast senescence.
登录
查看更多内容
影响因子：
5.3
作者：
ARCECI, RJ;KING, AAJ;WILSON, DB
通讯作者：
WILSON, DB
影响因子：
21.3
作者：
Jun, Joon-Il;Lau, Lester F.
通讯作者：
Lau, Lester F.
影响因子：
1.5
作者：
Acharya, Asha;Baek, Seung Tae;Banfi, Serena;Eskiocak, Banu;Tallquist, Michelle D.
通讯作者：
Tallquist, Michelle D.
影响因子：
11.8
作者：
Demaria, Marco;Ohtani, Naoko;Youssef, Sameh A.;Rodier, Francis;Toussaint, Wendy;Mitchell, James R.;Laberge, Remi-Martin;Vijg, Jan;Van Steeg, Harry;Dolle, Martijn E. T.;Hoeijmakers, Jan H. J.;de Bruin, Alain;Hara, Eiji;Campisi, Judith
通讯作者：
Campisi, Judith
影响因子：
56.9
作者：
NICHOLS, WW;MURPHY, DG;DWIGHT, SA
通讯作者：
DWIGHT, SA