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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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Research Article Cardiology Therapeutics

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

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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 4

CaMKII inhibition by CSB improves heart function after MI.

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CaMKII inhibition by CSB improves heart function after MI.
(A) Western b...
(A) Western blot images and quantification show the protein level of total CaMKII and phospho-CaMKII (pCaMKII) in P8 cardiac cell cultures treated with CSB for 4 days versus untreated control (n = 6 for each group, mean ± SD, paired 2-tailed Student’s t test). (B) Number of P8 cardiomyocytes in live culture relative to day 1 as quantified by the screening system (no treatment, n = 11; 1 μM KN62, n = 4; 5 μM KN62, n = 7; 10 μM KN62, n = 7; mean ± SEM, 1-way ANOVA and Dunnett’s post hoc test). (C) Western blot images and quantifications show the protein level of total CaMKII (lower panel) and pCaMKII (upper panel) in the ventricles of adult mice 5 days after MI (n = 3 for each group, mean ± SD, 1-way ANOVA and Sidak’s correction). Samples from uninjured mice were run in the same gel as MI + PBS and MI + CSB but were noncontiguous. (D) Cardiac EF of adult mice uninjured (n = 3) or injured and treated with PBS (n = 6) or KN62 (n = 6) up to 21 days after MI (mean ± SEM, 1-way ANOVA and Dunnett’s post hoc test). For all panels: *P < 0.05, **P < 0.01. NS, not significant.
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