Crosstalk between PML and p53 in response to TGF-β1: A new mechanism of cardiac fibroblast activation.
Crosstalk between PML and p53 in response to TGF-β1: A new mechanism of cardiac fibroblast activation.
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PML 和 p53 之间对 TGF-β1 的串扰：心脏成纤维细胞激活的新机制
DOI：
10.7150/ijbs.76214
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发表时间：
2023
影响因子：
9.2
通讯作者：
Cai BZ
中科院分区：
文献类型：
--
作者：
Huang D;Zhao D;Li M;Chang SY;Xue YD;Xu N;Li SJ;Tang NN;Gong LL;Liu YN;Yu H;Li QS;Li PY;Liu JL;Chen HX;Liu MB;Zhang WY;Zhao XM;Lang XZ;Li ZD;Liu Y;Ma ZY;Li JM;Wang N;Tian H;Cai BZ
心脏纤维化是多种心脏疾病中常见的病理性心脏重塑，其特征是心脏成纤维细胞的活化。我们之前的研究发现，早幼粒细胞白血病蛋白（PML）相关的 SUMO 过程是心脏肥大和心力衰竭的新调节因子。本研究旨在探讨PML在心脏成纤维细胞活化中的作用。在这里，我们发现经转化生长因子-β1 (TGF-β1) 处理的心脏纤维化组织和活化的心脏成纤维细胞中 PML 显着上调。功能获得和丧失实验表明，PML 影响 TGF-β1 治疗后心脏成纤维细胞的活化。进一步研究表明p53作为PML的转录调节因子，参与TGF-β1诱导PML表达增加和PML核体（PML-NBs）形成。 p53 的敲除或药物抑制对心脏成纤维细胞的活化产生抑制作用。我们进一步发现，PML 还可以通过抑制心脏成纤维细胞中泛素介导的蛋白酶体降解来稳定 p53。总的来说，这项研究表明 PML 与 p53 的串扰调节心脏成纤维细胞的激活，这为心脏纤维化提供了一种新的治疗策略。
Cardiac fibrosis is a common pathological cardiac remodeling in a variety of heart diseases, characterized by the activation of cardiac fibroblasts. Our previous study uncovered that promyelocytic leukemia protein (PML)-associated SUMO processes is a new regulator of cardiac hypertrophy and heart failure. The present study aimed to explore the role of PML in cardiac fibroblasts activation. Here we found that PML is significantly upregulated in cardiac fibrotic tissue and activated cardiac fibroblasts treated with transforming growth factor-β1 (TGF-β1). Gain- and loss-of-function experiments showed that PML impacted cardiac fibroblasts activation after TGF-β1 treatment. Further study demonstrated that p53 acts as the transcriptional regulator of PML, and participated in TGF-β1 induced the increase of PML expression and PML nuclear bodies (PML-NBs) formation. Knockdown or pharmacological inhibition of p53 produced inhibitory effects on the activation of cardiac fibroblasts. We further found that PML also may stabilize p53 through inhibiting its ubiquitin-mediated proteasomal degradation in cardiac fibroblasts. Collectively, this study suggests that PML crosstalk with p53 regulates cardiac fibroblasts activation, which provides a novel therapeutic strategy for cardiac fibrosis.
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影响因子：
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