Loading…

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

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...

Full description

Saved in:
Bibliographic Details
Published in:JCI insight 2019-11, Vol.4 (22)
Main Authors: Yifa, Oren, Weisinger, Karen, Bassat, Elad, Li, Hanjun, Kain, David, Barr, Haim, Kozer, Noga, Genzelinakh, Alexander, Rajchman, Dana, Eigler, Tamar, Umansky, Kfir Baruch, Lendengolts, Daria, Brener, Ori, Bursac, Nenad, Tzahor, Eldad
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.128025