小柯机器人

近日，澳大利亚Victor Chang心脏研究所Richard P. Harvey、Vaibhao Janbandhu等研究人员合作发现，Hif1a抑制心肌梗死后ROS诱导的心肌成纤维细胞增殖。2021年11月10日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员发现，心脏成纤维细胞（CF）和间质祖细胞比其他心脏间质群体更缺氧，表达更多的缺氧诱导因子1α（HIF-1α），并表现出糖代谢的增加。使用单细胞RNA测序（scRNA-seq）证明，CF特异性删除Hif-1a导致HIF-1靶基因表达减少，未受损伤的心脏中间质祖细胞增加，假性损伤后CF激活增加但没有增殖。然而，在心肌梗塞（MI）后，CF增殖增加了50%，并出现了过度的瘢痕和收缩功能障碍，这种情况在3D工程心脏微组织中得到了重复。

CF的增殖与较高的活性氧（ROS）有关，这也发生在用线粒体ROS发生因子MitoParaquat（MitoPQ）治疗的野生型小鼠身上。线粒体靶向抗氧化剂MitoTEMPO挽救了Hif-1a突变体表型。因此，CF中的HIF-1α通过对线粒体ROS的调节，对缺血后CF的过度激活和增殖提供了一个关键的刹车机制。CF是心血管疾病中设计抗氧化疗法的潜在细胞靶标。

附：英文原文

Title: Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction

Author: Vaibhao Janbandhu, Vikram Tallapragada, Ralph Patrick, Yanzhen Li, Dhanushi Abeygunawardena, David T. Humphreys, Ella M.M.A. Martin, Alexander O. Ward, Osvaldo Contreras, Nona Farbehi, Ernestene Yao, Junjie Du, Sally L. Dunwoodie, Nenad Bursac, Richard P. Harvey

Issue&Volume: 2021-11-10

Abstract: We report that cardiac fibroblasts (CFs) and mesenchymal progenitors are more hypoxicthan other cardiac interstitial populations, express more hypoxia-inducible factor1α (HIF-1α), and exhibit increased glycolytic metabolism. CF-specific deletion ofHif-1a resulted in decreased HIF-1 target gene expression and increased mesenchymal progenitorsin uninjured hearts and increased CF activation without proliferation following shaminjury, as demonstrated using single-cell RNA sequencing (scRNA-seq). After myocardialinfarction (MI), however, there was ～50% increased CF proliferation and excessivescarring and contractile dysfunction, a scenario replicated in 3D engineered cardiacmicrotissues. CF proliferation was associated with higher reactive oxygen species(ROS) as occurred also in wild-type mice treated with the mitochondrial ROS generatorMitoParaquat (MitoPQ). The mitochondrial-targeted antioxidant MitoTEMPO rescued Hif-1a mutant phenotypes. Thus, HIF-1α in CFs provides a critical braking mechanism againstexcessive post-ischemic CF activation and proliferation through regulation of mitochondrialROS. CFs are potential cellular targets for designer antioxidant therapies in cardiovasculardisease.

DOI: 10.1016/j.stem.2021.10.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00421-5

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