Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Recently published
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
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.
View: Text | PDF
Research Article Cardiology Therapeutics

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

  • Text
  • PDF
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

×

Figure 5

CSB improves cardiomyocyte calcium handling and contraction in NRVM cardiobundles.

Options: View larger image (or click on image) Download as PowerPoint
CSB improves cardiomyocyte calcium handling and contraction in NRVM card...
(A) Representative Western blots and quantification showing decreased protein levels of total CaMKII and phospho-CaMKII (pCaMKII) in cardiobundles treated with CSB versus no treatment (no treatment, n = 6; CSB, n = 4; mean ± SD, unpaired 2-tailed Student’s t test). Data were obtained from 2 separate NRVM isolations. (B) Representative calcium transients in cardiobundles during 5-Hz pacing recorded by GCaMP6 sensor (shown as change in fluorescence intensity relative to baseline, df/f). (C) Representative isometric twitch force traces in cardiobundles during 5-Hz pacing. (D and E) Calcium df/f in cardiobundles paced at 5 Hz (D) or 2 Hz (E) (no treatment: 5 Hz n = 4, 2 Hz n = 4; CSB: 5 Hz n = 6, 2 Hz n = 6; mean ± SD, unpaired 2-tailed Student’s t test). (F) Twitch amplitude (max force) in cardiobundles paced at 5 Hz treated with CSB versus untreated control; data presented relative to no treatment (no treatment, n = 7; CSB, n = 6; mean ± SD, unpaired 2-tailed Student’s t test). Data were obtained from 2 separate NRVM isolations. (G) Twitch duration in CSB-treated cardiobundles versus untreated control paced at 2 Hz (no treatment, n = 7; CSB, n = 6; mean ± SD, unpaired 2-tailed Student’s t test). Data were obtained from 2 separate NRVM isolations. In all cardiobundle experiments CSB was administered at a concentration of 50 μM. For all panels: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Follow JCI Insight:
Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts