Introduction:
Cardiac remodeling post myocardial infarction (MI) can be a critical determinant of outcome for patients with MI. Well-contained inflammation results in successful infarct healing while excessive inflammation cause adverse remodeling which leads to heart failure. Macrophages are important participants in inflammation, helping resolve pro-inflammatory reactions and performing reparative processes. Reprogramming macrophages towards a resolving and reparative phenotype is a potential therapeutic approach. We hypothesized that IL4/IL13-induced, alternatively activated macrophages (M2) have an important role in cardiac remodeling post-MI, and we tested this hypothesis in a mouse model of MI using myeloid-specific IL4 receptor α knockout mice (MyIL4RaKO).
Methods:
MyIL4RaKO mice were generated using IL4Ra
flox/flox
;LysM-Cre. MI was induced by ligating the left anterior descending coronary artery. Hearts were cut into 1mm sections, and then stained by tetrazolium chloride for infarct size measurement. Evenly spaced radians were taken through the infarct with the center of left ventricle in 5μm heart sections, and the average infarct thickness was calculated. qPCR was used to determine gene expression. Echocardiography was performed at baseline and 3 weeks post MI.
Results:
Initial infarct size was not affected by IL4Ra knockout but at 1-week post MI, infarct size of MyIL4RaKO mice (16.54 ± 2.433, n=11) was shown significantly smaller than that of FC mice (24.96 ± 2.005, n=15) showing changes in remodeling (p= 0.0129). Changes in remodeling continued and at 3-week post MI, infarct thickness of MyIL4RaKO mice (0.2171 ± 0.01053, n=6) was significantly increased, compared with that of FC mice (0.3508 ± 0.03629, n=8, p= 0.0094). These changes were accompanied by MyIL4RaKO mice also showed lower level of fibrosis markers: Col1A1 and Plod2. A significantly lower ejection fraction was observed in MyIL4RaKO mice (25.46 ± 3.749, n=5) compared with FC mice (37.90 ± 2.309, n=5) at 3 weeks (p= 0.0223).
Conclusions:
Myeloid-specific IL4Ra knockout results in alteration of remodeling, altered fibrosis and decreased cardiac function post MI, although the cardiac hypertrophy did not show significant change.
IMPACT OF SODIUM GLUCOSE COTRANSPORTER 2 INHIBITORS ON CARDIAC REMODELING AND EXERCISE CAPACITY AFTER ACUTE MYOCARDIAL INFARCTION
