IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells

• Published in: Molecular therapy 2019-01, Vol.27 (1), p.46-58
• Main Authors: Heinen, Andre, Nederlof, Rianne, Panjwani, Priyadarshini, Spychala, André, Tschaidse, Tengis, Reffelt, Heiko, Boy, Johannes, Raupach, Annika, Gödecke, Stefanie, Petzsch, Patrick, Köhrer, Karl, Grandoch, Maria, Petz, Anne, Fischer, Jens W., Alter, Christina, Vasilevska, Jelena, Lang, Philipp, Gödecke, Axel
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bone marrow; Cardiac function; cardiac remodeling; Cardiomyocytes; Cardiovascular disease; Cell cycle; Chemokines; Coronary vessels; Cytokines; Echocardiography; Flow Cytometry; Gene expression; Heart; Heart attacks; Inflammation; Insulin; insulin-like growth factor 1; Insulin-like growth factor I; Insulin-Like Growth Factor I - therapeutic use; Ischemia; macrophage polarization; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid cells; Myeloid Cells - drug effects; Myocardial infarction; Myocardial Infarction - drug therapy; Neutrophils; Original; Phenotypes; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Software; Statistical analysis; Veins & arteries
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.10.020

Insulin-like growth factor 1 (IGF1) is an anabolic hormone that controls the growth and metabolism of many cell types. However, IGF1 also mediates cardio-protective effects after acute myocardial infarction (AMI), but the underlying mechanisms and cellular targets are not fully understood. Here we demonstrate that short-term IGF1 treatment for 3 days after AMI improved cardiac function after 1 and 4 weeks. Regional wall motion was improved in ischemic segments, scar size was reduced, and capillary density increased in the infarcted area and the border zone. Unexpectedly, inducible inactivation of the IGF1 receptor (IGF1R) in cardiomyocytes did not attenuate the protective effect of IGF1. Sequential cardiac transcriptomic analysis indicated an altered myeloid cell response in the acute phase after AMI, and, notably, myeloid-cell Igf1r−/− mice lost the protective IGF1 function after I/R. In addition, IGF1 induced an M2-like anti-inflammatory phenotype in bone marrow-derived macrophages and enhanced the number of anti-inflammatory macrophages in heart tissue on day 3 after AMI in vivo. In summary, modulation of the acute inflammatory phase after AMI by IGF1 represents an effective mechanism to preserve cardiac function after I/R. Heinen et. al. demonstrate that insulin-like growth factor 1 (IGF1) reduces scar size and improves cardiac function after myocardial infarction. This protective effect is independent of IGF1 signaling in cardiac myocytes but involves IGF1-dependent modulation of myeloid cells and enhanced accumulation of anti-inflammatory macrophages in the infarcted heart.