Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
JCI Insight. 2019 Nov 14;4(22):128025. doi: 10.1172/jci.insight.128025.
The adult mammalian heart regenerates poorly after injury and, as a result, ischemic heart diseases are among the leading causes of death worldwide. The recovery of the injured heart is dependent on orchestrated repair processes including inflammation, fibrosis, cardiomyocyte survival, proliferation, and contraction properties that could be modulated in patients. In this work we designed an automated high-throughput screening system for small molecules that induce cardiomyocyte proliferation in vitro and identified the small molecule Chicago Sky Blue 6B (CSB). Following induced myocardial infarction, CSB treatment reduced scar size and improved heart function of adult mice. Mechanistically, we show that although initially identified using in vitro screening for cardiomyocyte proliferation, in the adult mouse CSB promotes heart repair through (i) inhibition of CaMKII signaling, which improves cardiomyocyte contractility; and (ii) inhibition of neutrophil and macrophage activation, which attenuates the acute inflammatory response, thereby contributing to reduced scarring. In summary, we identified CSB as a potential therapeutic agent that enhances cardiac repair and function by suppressing postinjury detrimental processes, with no evidence for cardiomyocyte renewal.
成年哺乳动物的心脏在受伤后再生能力很差，因此，缺血性心脏病是全球主要的死亡原因之一。受伤心脏的恢复依赖于协调的修复过程，包括炎症、纤维化、心肌细胞存活、增殖和收缩特性，这些特性可以在患者中进行调节。在这项工作中，我们设计了一种用于体外诱导心肌细胞增殖的小分子的自动化高通量筛选系统，并鉴定出小分子芝加哥天青石 6B（CSB）。在诱导心肌梗死后，CSB 处理减少了成年小鼠的疤痕大小并改善了心脏功能。从机制上讲，我们表明，尽管最初是使用体外筛选来检测心肌细胞增殖，但在成年小鼠中，CSB 通过（i）抑制 CaMKII 信号通路来促进心脏修复，该信号通路可改善心肌细胞的收缩性；和（ii）抑制中性粒细胞和巨噬细胞的激活，从而减轻急性炎症反应，从而减少疤痕形成。总之，我们发现 CSB 是一种潜在的治疗药物，通过抑制损伤后有害的过程来增强心脏修复和功能，而没有证据表明心肌细胞更新。
