Content area
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 through 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 and reduces scar size. In addition, we demonstrate that CSB effect is not restricted to the heart, as it delayed differentiation and increased proliferation of skeletal muscle cells in vitro. In summary, we identified CSB as a novel potential therapeutic agent that enhances cardiac repair and function by suppressing post-injury detrimental processes, with no evidence for cardiomyocyte renewal.
