Abstract 3553: Preserved Cardiac Function after Myocardial Infarction in Mice Lacking the Frizzled-2 Gene
Myocardial infarction (MI) leads to death of cardiomyocytes in the ischemic areas, which evokes a wound healing process strongly influenced by myofibroblasts. Inadequate healing leads to loss of cardiac function due to dilatation of the infarcted ventricle. Previously, we reported that frizzled-2 receptor is upregulated in myofibroblasts, suggesting a role of Wnt/frizzled-signaling in infarct healing. Here we created a novel conditional frizzled-2 knockout mouse in which frizzled-2 receptor was ubiquitously deleted by cross-breeding with a mouse that expresses Cre recombinase under the CMV promoter. MI was induced by ligation of the left ascending coronary artery; cardiac function (baseline and after dobutamine stimulation) and infarct dimensions were studied in homozygous frizzled-2 knockout (fz −/−) mice and their wildtype (wt) littermates at 7, 14 and 28 days post-MI. Myofibroblast numbers were determined in histological sections stained with anti-α-smooth muscle actin antibody. No differences in infarct size were observed between fz −/− and wt mice. In sham-operated animals, dobutamine increased blood pressure (mmHg/s, mean±S.E.M.) by 130±23% in fz −/−mice and by 166±29% in wt mice. At 28 days post-MI, dobutamine increased blood pressure by 230±93% in fz −/− mice and only by 79±36% in wt mice. Thus, cardiac function was better preserved in fz −/− than in wt mice. Infarct area was less thin in fz −/− mice: the ratio between the total area and length of the infarct area was 0.55±0.06 for fz −/− and 0.43±0.06 for wt mice. The number of myofibroblasts in the infarct area was maximally 3.4-fold higher at 28 days post-MI in fz −/− than in wt mice. Collagen content in infarct area was more prominently increased in fz −/− mice at 7 days after MI, but was thereafter lower than that of wt mice. In conclusion, deletion of frizzled-2 receptor attenuates the thinning of infarcted ventricle and preserves cardiac function after MI, apparently by a higher number of myofibroblasts in the infarct area and the altered synthesis of extracellular matrix. Our data suggest that frizzled-2 receptor antagonists could be useful to improve infarct healing after MI.
This study was supported by NWO grant 917 36 320.