Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner.
Cardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner.
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DOI：
10.1038/s41467-020-20361-3
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发表时间：
2021-01-04
影响因子：
16.6
通讯作者：
van Rooij E
中科院分区：
文献类型：
--
作者：
Gladka MM;Kohela A;Molenaar B;Versteeg D;Kooijman L;Monshouwer-Kloots J;Kremer V;Vos HR;Huibers MMH;Haigh JJ;Huylebroeck D;Boon RA;Giacca M;van Rooij E
心肌梗死引起的血液供应中断是梗死面积和随后功能恶化的关键决定因素。因此，通过血管网络的修复来识别增强心脏修复的因素具有重要意义。在这里，我们发现转录因子锌指E-box-binding homeobox 2 （ZEB2）在应激心肌细胞中增加，并诱导心肌细胞和内皮细胞之间的心脏保护性交叉对话，以促进缺血后的血管生成。单细胞测序显示ZEB2在损伤心肌细胞中富集。心肌细胞特异性的ZEB2缺失会导致心肌收缩力和心肌梗死后的梗死愈合受损，而心肌细胞特异性的ZEB2过表达则会改善心肌细胞的存活和心功能。我们发现胸腺素β4 （TMSB4）和原胸腺素α (PTMA)是心肌细胞释放的主要旁分泌因子，通过增强内皮细胞的迁移来刺激血管生成，并在体内模型中得到了验证。将ZEB2治疗性递送至梗死心脏心肌细胞可诱导TMSB4和PTMA的表达，从而促进血管生成，防止心功能障碍。这些发现揭示了ZEB2在缺血性损伤过程中是一个有益因子，这可能为确定新的治疗方法带来希望。ZEB2转录因子在应激状态下的心肌细胞亚群中增加，从而诱导损伤后的心脏保护作用。在这里，作者表明，治疗性递送ZEB2可以预防缺血性损伤后的心功能障碍，并促进促血管生成信号的激活。
The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin β4 (TMSB4) and Prothymosin α (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies. ZEB2 transcription factor is increased in a subset of cardiomyocytes during stress to induce cardioprotective effects after injury. Here the authors show that therapeutic delivery of ZEB2 prevents cardiac dysfunction after ischemic damage and promotes the activation of pro-angiogenic signals.
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影响因子：
--
作者：
Shah R;Reyes-Gordillo K;Cheng Y;Varatharajalu R;Ibrahim J;Lakshman MR
通讯作者：
Lakshman MR
影响因子：
37.8
作者：
Kehat I;Molkentin JD
通讯作者：
Molkentin JD
DOI：
10.1161/atvbaha.112.245134
发表时间：
2012-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Cheng Z;DiMichele LA;Hakim ZS;Rojas M;Mack CP;Taylor JM
通讯作者：
Taylor JM
影响因子：
7.2
作者：
Cannavo, Alessandro;Rengo, Giuseppe;Esposito, Giovanni
通讯作者：
Esposito, Giovanni
影响因子：
16.6
作者：
Smart, Nicola;Dube, Karina N.;Riley, Paul R.
通讯作者：
Riley, Paul R.