Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide.
Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide.
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心肌细胞 FoxP3 参与心脏重塑过程中 Parkin 介导的线粒体自噬以及雷公藤甲素的调节作用
DOI：
10.7150/thno.71102
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Zhang HG
中科院分区：
文献类型：
--
作者：
Pan XC;Xiong YL;Hong JH;Liu Y;Cen YY;Liu T;Yang QF;Tao H;Li YN;Zhang HG
原理：Forkhead/Winged Helix转录因子P3(FoxP3)是一种广泛研究的转录因子，可以维持T细胞的活性，但心肌细胞FoxP3是否参与心脏重构(CR)尚不清楚。本研究从吞噬有丝分裂的角度探讨心肌细胞FoxP3在CR中的作用。方法：采用雄性C57小鼠和FoxP3DTR小鼠，分别用血管紧张素II(AngII)和异丙肾上腺素(Iso)在体外诱导CR。苏木精-伊红染色和Masson染色观察组织学变化。用免疫组织化学、免疫荧光、免疫印迹和实时定量聚合酶链式反应检测细胞分子变化。通过透射电子显微镜和共定位观察细胞有丝分裂的形态。通过siRNA或腺相关病毒(AAV)调控基因的表达。通过共定位、免疫沉淀(IP)和染色质IP检测分子间相互作用。结果：心肌细胞FoxP3的表达和核转位在CR组下调，而雷公藤甲素(TP)治疗后上调。在小鼠左心室(LV)重塑过程中，心肌内自噬持续激活，TP可显著减弱自噬作用。Angii诱导了大量的有丝分裂吞噬，其特征是激活了依赖于自噬调节蛋白5(ATG5)的自噬通量。关键的是，Parkin被认为是介导心肌有丝分裂的主要接头，并对TP的作用负责。此外，FoxP3还下调了Parkin的表达，并抑制了AngII诱导的心脏有丝分裂。我们发现，在FoxP3缺陷的LV中，丝裂原吞噬显着增加，TP的抑制作用完全逆转。在机制上，FoxP3与Parkin启动子所涉及的激活转录4(ATF4)结合基序下游的一个基序相互作用，劫持游离核ATF4以降低CR中Parkin mRNA的表达。结论：心肌细胞FoxP3可负性调节Parkin介导的CR有丝分裂，恢复心肌细胞FoxP3活性可抑制过度的心肌有丝分裂，从而起到保护心脏的作用。
Rationale: Forkhead/winged helix transcriptional factor P3 (FoxP3) is a well-studied transcription factor that maintains the activity of T cells, but whether cardiomyocytic FoxP3 participates in cardiac remodeling (CR) remains unclear. The present study was to investigate the role of cardiomyocytic FoxP3 in CR from the perspective of mitophagy. Methods: CR was induced by angiotensin II (AngII) in vitro, or by isoproterenol (Iso) in vivo using male C57 mice or FoxP3DTR mice. Histological changes were observed by hematoxylin-eosin and Masson staining. Molecular changes were detected by immunohistochemistry, immunofluorescence, immunoblotting, and real-time PCR. Mitophagy was shaped by transmission electron microscopy and co-localization. The mRNA expression was operated by siRNA or adeno associated virus (AAV). Molecular interactions were detected by co-localization, immunoprecipitation (IP), and chromatin IP. Results: The expression and nuclear translocation of cardiomyocytic FoxP3 were downregulated in CR, while they were upregulated after triptolide (TP) treatment. In left ventricle (LV) remodeling in mice, autophagy was activated continuously in the myocardium, and TP significantly attenuated it. AngII induced massive mitophagy characterized by the activation of autophagy regulatory protein 5 (Atg5)-dependent autophagic flux. Critically, Parkin was identified as the main adaptor mediated myocardial mitophagy and was responsible for the effect of TP. Moreover, FoxP3 was responsible for the downregulation of Parkin and inhibited AngII-induced cardiac mitophagy. We found that mitophagy increased significantly and the inhibition of TP treatment reversed completely in FoxP3-deficient LVs. Mechanistically, FoxP3 interacted with a motif located downstream of the activating transcription 4 (ATF4)-binding motif involved in the promoter of Parkin and hijacked free nuclear ATF4 to decrease Parkin mRNA expression in CR. Conclusion: Cardiomyocytic FoxP3 could negatively regulate Parkin-mediated mitophagy in CR, and restoring cardiomyocytic FoxP3 activity provided a cardioprotective strategy by inhibiting excessive cardiac mitophagy.
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