Abstract 11433: Postinfarction Cardiac Remodeling Normally Proceeds in Granulocyte Colony-Stimulating Factor Knockout Mice
Treatment with granulocyte colony-stimulating factor (G-CSF) has been reported to mitigate postinfarction cardiac remodeling. We here examined how the postinfarction remodeling proceeds in the hearts of G-CSF-null mice, of which outcome we hypothesized to be miserable. We generated myocardial infarction in G-CSF-knockout (KO) mice and wild-type (WT) mice by ligation of the left coronary artery. The acute infarct size was similar at 24 h after ligation between the groups, where the incidence of in situ nick-end labeling (TUNEL)-positive cardiomyocytes was similar while the infiltrating leukocytes were significantly fewer in KO mice (n = 6 each). Somewhat surprisingly, at the chronic stage (4 weeks postinfarction), there was no difference in the left ventricular dimension, function and histological findings including the infarct size and myocardial vascular density between the groups (n = 6 each). Because it was contrary to our hypothesis, we next investigated the changes in major angiogenesis growth factors such as angiopoientin-1, hepatocyte growth factor, hypoxia induced factor-1 alpha, insulin-like growth factor-1, vascular endothelial growth factor (VEGF) in postinfarction hearts. As a result, biochemical analyses revealed a markedly increased expression of VEGF in the hearts of KO mice compared with WT mice (n = 6 each). The findings suggest a possibility that overexpressed VEGF might have compensated for the defect of G-CSF in KO mice. To check this hypothesis, we next inhibited the VEGF signal using an anti-VEGF antibody bevacizumab. Then the cardiac remodeling was significantly aggravated at the chronic stage, and the immunostaining showed scarce vascular development, reduced cell proliferation activity, and increased apoptosis in the granulation tissue of the bevacizumab-treated hearts at the subacute stage (4 days postinfarction), which might have contributed to the aggravation of cardiac remodeling during the chronic stage. In conclusion, G-CSF-KO mice unexpectedly displayed normal process of postinfarction cardiac remodeling. Overexpressed VEGF in the KO mice is suggested to compensate for the deficit of G-CSF through enhancement of neovascularization in the postinfarction heart.
Author Disclosures: K. Morishita: None. G. Takemura: None. A. Tsujimoto: None. H. Kanamori: None. I. Kawamura: None. A. Mikami: None. H. Okada: None. T. Takeyama: None. T. Kawaguchi: None. T. Watanabe: None. K. Goto: None. A. Ogino: None. M. Morishita: None. H. Ushikoshi: None. M. Kawasaki: None. S. Ogura: None. S. Minatoguchi: None. S. Minatoguchi: None.
- © 2014 by American Heart Association, Inc.