The small molecule Chicago Sky Blue promotes heart repair following myocardial infarction in mice
Oren Yifa, … , Nenad Bursac, Eldad Tzahor
Oren Yifa, … , Nenad Bursac, Eldad Tzahor
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e128025. https://doi.org/10.1172/jci.insight.128025.
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Categories: Research Article Cardiology Therapeutics

The small molecule Chicago Sky Blue promotes heart repair following myocardial infarction in mice

Abstract

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.

Authors

Oren Yifa, Karen Weisinger, Elad Bassat, Hanjun Li, David Kain, Haim Barr, Noga Kozer, Alexander Genzelinakh, Dana Rajchman, Tamar Eigler, Kfir Baruch Umansky, Daria Lendengolts, Ori Brener, Nenad Bursac, Eldad Tzahor

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Figure 1

Small-molecule screen identifies Chicago Sky Blue 6B as a molecule that induces cardiomyocyte proliferation.

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Small-molecule screen identifies Chicago Sky Blue 6B as a molecule that ...
(A) Schematic representation of the high-throughput screening system. P8 cardiac cells were plated in 384-well plates and introduced to different small molecules. Using automated high-throughput microscopy, the cardiomyocytes in each well were counted daily and compared to the number of cardiomyocytes in the same well in the beginning of the experiment. (B) Repeated measurements for validation of the screen results. Number of P8 cardiomyocytes in live culture relative to day 2 (no treatment, n = 20; Chicago Sky Blue 6B [CSB], n = 16; data are presented as mean ± SEM, unpaired 2-tailed Student’s t test). (C) Percentage of Ki67+ P8 cardiomyocytes normalized to total cardiomyocytes after 4-day incubation with CSB (no treatment, n = 11; CSB, n = 7; mean ± SD, unpaired 2-tailed Student’s t test). (D) Percentage of multinucleated P8 cardiomyocytes normalized to total cardiomyocytes after 4-day incubation with CSB (n = 6 for each group, mean ± SD, paired 2-tailed Student’s t test). (E) Percentage of Ki67+ nuclei normalized to total nuclei in P8 cardiac cells after 4-day incubation with CSB (n = 5 for each group, mean ± SD, paired 2-tailed Student’s t test). (F) Number of P8 cardiomyocytes in live culture relative to day 2. Cells were treated with compounds that share structural similarity with CSB (no treatment, n = 20; CSB, n = 16; S9, n = 4; S4, n = 6; R3, n = 3; mean ± SEM, 1-way ANOVA and Dunnett’s post hoc test). The colored asterisks represent the significance of the difference for each compound from the nontreated culture. The data for no treatment and CSB-treated cultures in panels B and F are an average of the same samples. For all panels: *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant.