Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Wound Repair Regen. 2021 Mar;29(2):211-224. doi: 10.1111/wrr.12892. Epub 2021 Jan 20.
In humans, myocardial infarction (MI) is associated with irreversible damage to heart tissue, resulting in increased morbidity and mortality in patients. By comparison, the zebrafish (Danio rerio) is capable of repairing damaged and injured hearts by activating a full regenerative response. By studying model organisms that can regenerate loss heart tissue following injury, such as the zebrafish, a greater insight will be gained into the molecular pathways that can induce and sustain a regenerative response following injury. There is hope that such information may lead to new treatments or therapies aimed at stimulating a better regenerative response in humans that have suffered heart attacks. Recent findings in zebrafish have highlighted an important role for sustained elevated levels of Reactive Oxygen Species (ROS), including hydrogen peroxide (H O ) in the promotion of a regenerative response. Given that elevated levels of H O can be harmful, simply elevating ROS levels directly may not be easy or practical to translate clinically. An alternative approach would be to identify the critical downstream targets of ROS in the promotion of heart regeneration, and then target these clinically using drugs. One such family of potential downstream targets of ROS during heart regeneration are the family of protein tyrosine phosphatases (PTPs), which are known to be exquisitely sensitive to redox regulation and whose inhibition have been linked to the promotion of heart regeneration in zebrafish. In this review, we present an overview of the zebrafish as a model organism for studying cardiac regeneration, including the molecular mechanisms by which cardiac regeneration occurs in response to injury. We then present recent findings linking elevated ROS levels to heart regeneration and their potential downstream targets, the PTPs, including protein tyrosine phosphatase 1B (PTP1B) and the dual specificity phosphatase 6 (DUSP6) in the promotion of heart regeneration.
在人类中，心肌梗死（MI）与心脏组织的不可逆转损伤有关，导致患者的发病率和死亡率增加。相比之下，斑马鱼（Danio rerio）能够通过激活完全再生反应来修复受损和受伤的心脏。通过研究能够在受伤后再生丢失的心脏组织的模式生物，如斑马鱼，可以更深入地了解可以诱导和维持受伤后再生反应的分子途径。人们希望这些信息可能会导致针对遭受心脏病发作的人类的新治疗或疗法，旨在刺激更好的再生反应。最近在斑马鱼中的发现强调了持续高水平的活性氧物种（ROS），包括过氧化氢（H2O2）在促进再生反应中的重要作用。鉴于 H2O2 的水平升高可能是有害的，直接提高 ROS 水平可能不容易或不切实际地在临床上转化。另一种方法是确定 ROS 在促进心脏再生中的关键下游靶标，然后使用药物在临床上靶向这些靶标。在心脏再生过程中，ROS 的一个潜在下游靶标家族是蛋白酪氨酸磷酸酶（PTP）家族，众所周知，它们对氧化还原调节非常敏感，其抑制与斑马鱼心脏再生的促进有关。在这篇综述中，我们介绍了斑马鱼作为研究心脏再生的模型生物的概述，包括心脏再生对损伤的分子机制。然后，我们介绍了最近的发现，将高水平的 ROS 与心脏再生及其潜在的下游靶标联系起来，即蛋白酪氨酸磷酸酶 1B（PTP1B）和双特异性磷酸酶 6（DUSP6）在促进心脏再生中的作用。
