Insulin‐like growth factor 1 preserves cardiac function after myocardial infarction by affecting myeloid cells
Authors: Nederlof Rianne , Heinen Andre , Spychala Andre , Panjwani Priyadarshini , Tschaidse Tengis , Gödecke Axel 
Published: June 2021

Insulin‐like growth factor (IGF1) controls growth and metabolism of many cell types. In addition, IGF1 has been shown to provide cardioprotective effects after acute myocardial infarction (AMI). However, the cell type and mechanisms involved are not yet fully understood.

Mice were exposed to 45 min LAD occlusion, followed by 4 weeks reperfusion. At the end of ischemia mice were injected with vehicle (Con) or IGF1 (40 ng/g ip), followed by continues treatment for 3 days via osmotic mini pumps (1 μg/g/d sc.). Cardiac function, determined by echocardiography at baseline and 1 and 4 weeks after ischemia, showed no differences at baseline in all mouse lines studied. IGF1 treatment improved cardiac function after 1 and 4 weeks in wild‐type mice ((EF, week 4: 49±4% (IGF1) vs 36±8% (Con)), but also in inducible cardiomyocyte‐specific IGF1‐receptor (IGF1R) KO mice (48±5% (IGF1) vs 35±5% (Con)). However, in myeloid cell specific IGF1R KO mice IGF1 was no longer protective (36±8% (IGF1) vs 38±8% (Con)), indicating that myeloid cells are responsible for the protective effect of IGF1 after MI. In addition, micro‐array analysis of the infarct area of the heart showed that mostly myeloid cell related pathways were altered in IGF treated mice 1 and 2 days after AMI.

To look further into the mechanism involved, in vitro and subacute experiments were performed. FACS and qPCR analysis showed that treatment of monocyte derived macrophages with IGF1 induced macrophage polarization to macrophages with a reparative M2‐like phenotype, characterized by an increase in mannose receptor (CD206), arginase and resistin‐like α. Also, in vivo FACS analysis of the heart showed an increase in M2‐like (CD206+) macrophages in IGF1 treated mice 3 days after AMI (152 777±13510 (IGF1) vs 108 071±14023 (Con) cells per heart) without affecting total macrophage number. In these mice, no effects on the amount of lymphocytes or monocytes were observed in blood or heart. A trend towards an increased number of neutrophils in the heart was seen after IGF treatment (272 120±42478 (IGF1) vs 198 122±31741 (Con) cells per heart), without an effect on neutrophil amount in blood. In addition, one week after AMI, i.e. a timepoint where functional cardiac improvement was observed in echo analysis, histological analysis of scar size showed a significant reduction in scar size after IGF1 treatment (9.2±4% (IGF1) vs. 14.7±3.9% (Con) of left ventricle). This was accompanied by an increased vessel formation in the scar (654±132 (IGF1) vs 495±94 (Con) CD31+ cells/mm2) and borderzone (1676±72 (IGF1) vs 1467±110 (Con)) after IGF1 treatment.

Interestingly, short term no protective effects of IGF1 were observed. IGF1 treatment did not reduce infarct size 2 hours after AMI (38±10% (IGF1) vs. 39±11% (Con) of left ventricle).

Short term IGF1 treatment improves cardiac function in the subacute phase after AMI by affecting myeloid cells. This effect was independent of the IGF1R in cardiomyocytes. IGF1 treatment increases the amount of reparative M2 macrophages, and may thereby improve vasculature and reduce scar size.

Support or Funding Information

Funded by SFB1116/A06

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.