Over 17 million yearly fatalities are attributed to cardiovascular diseases and the majority are due to myocardial infarctions (MI). Having just one MI event increases the yearly mortality risk by 5% for the remaining lifetime. Adult cardiac myocytes have a limited capacity to regenerate and instead, scarring occurs at the site of damage. Whereas in neonates, damaged cardiac myocytes regenerate, healing the damaged tissue. Understanding the difference between adult and neonatal cardiomyocytes regenerative mechanisms could help promote tissue repair following MI.
Previous research has demonstrated that MI induces an inflammatory response to stimulate regeneration. It is well known that the kynurenine pathway (KP) and the inflammatory response influence each other via aryl hydrocarbon receptor (AHR) activity. In this study, Dr. Donghong Zhang and associates delineate the role of the KP in neonatal cardiac regeneration, published in Nature Communications. Following cardiac apical resection, there was a rapid but transient increase in indolamine 2,3 dioxygenase-1 (IDO1), which resulted in increased kynurenine (KYN) levels and decreased tryptophan. Furthermore, there was less fibrosis (i.e. better recovery) following apical resection in IDO1-intact (wild-type control) compared to IDO1-KO mice. Cardiomyocytes isolated from IDO1-KO mice exhibited increased inflammatory pathways signaling with an attenuated proliferation of cardiomyocytes. These data demonstrate that KYN generated by IDO1 activity promotes regeneration following cardiac damage. KYN colocalized with the AHR in areas of regeneration following apical resection. The binding of KYN to the AHR was associated with increased angiogenesis. Taken together, IDO1-derived KYN signaling plays a crucial role in neonatal cardiac angiogenesis. More research is required to determine whether KYN-targeted therapeutics promote regeneration in adult cardiomyocytes.