Morishita Kentaro, Takemura Genzou, Tsujimoto Akiko, Kanamori Hiromitsu, Okada Hideshi, Chousa Mitsuhiro, Ushimaru Seiko, Mikami Atsushi, Kawamura Itta, Takeyama Toshiaki, Kawaguchi Tomonori, Watanabe Takatomo, Goto Kazuko, Morishita Megumi, Ushikoshi Hiroaki, Kawasaki Masanori, Ogura Shinji, Minatoguchi Shinya
Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Internal Medicine, Asahi University School of Dentistry, Mizuho, Japan.
Am J Pathol. 2015 Jul;185(7):1899-911. doi: 10.1016/j.ajpath.2015.03.018. Epub 2015 May 11.
Treatment with granulocyte colony-stimulating factor (G-CSF) reportedly mitigates postinfarction cardiac remodeling and dysfunction. We herein examined the effects of G-CSF knockout (G-CSF-KO) on the postinfarction remodeling process in the hearts of mice. Unexpectedly, the acute infarct size 24 hours after ligation was similar in the two groups. At the chronic stage (4 weeks later), there was no difference in the left ventricular dimension, left ventricular function, or histological findings, including vascular density, between the two groups. In addition, expression of vascular endothelial growth factor (VEGF) was markedly up-regulated in hearts from G-CSF-KO mice, compared with wild-type mice. Microarray failed in detecting up-regulation of VEGF mRNA, whereas G-CSF administration significantly decreased myocardial VEGF expression in mice, indicating that G-CSF post-transcriptionally down-regulates VEGF expression. When G-CSF-KO mice were treated with an anti-VEGF antibody (bevacizumab), cardiac remodeling was significantly aggravated, with thinning of the infarct wall and reduction of the cellular component, including blood vessels. In the granulation tissue of bevacizumab-treated hearts 4 days after infarction, vascular development was scarce, with reduced cell proliferation and increased apoptosis, which likely contributed to the infarct wall thinning and the resultant increase in wall stress and cardiac remodeling at the chronic stage. In conclusion, overexpression of VEGF may compensate for the G-CSF deficit through preservation of cellular components, including blood vessels, in the postinfarction heart.
据报道，粒细胞集落刺激因子（G-CSF）治疗可减轻心肌梗死后的心脏重塑和功能障碍。我们在此研究了G-CSF基因敲除（G-CSF-KO）对小鼠心脏梗死后重塑过程的影响。出乎意料的是，两组在结扎后24小时的急性梗死面积相似。在慢性期（4周后），两组之间的左心室尺寸、左心室功能或组织学结果（包括血管密度）没有差异。此外，与野生型小鼠相比，G-CSF-KO小鼠心脏中血管内皮生长因子（VEGF）的表达明显上调。基因芯片未能检测到VEGF mRNA的上调，而给予G-CSF可显著降低小鼠心肌VEGF表达，表明G-CSF在转录后下调VEGF表达。当用抗VEGF抗体（贝伐单抗）治疗G-CSF-KO小鼠时，心脏重塑明显加重，梗死壁变薄，包括血管在内的细胞成分减少。在梗死4天后用贝伐单抗治疗的心脏肉芽组织中，血管发育稀少，细胞增殖减少，凋亡增加，这可能导致梗死壁变薄以及慢性期壁应力增加和心脏重塑。总之，VEGF的过表达可能通过保留梗死心脏中的细胞成分（包括血管）来弥补G-CSF的不足。
