Circulation. 2004;109:2572-2580
Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000129770.93985.3E
Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000129770.93985.3E
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(Circulation. 2004;109:2572-2580.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Acceleration of the Healing Process and Myocardial Regeneration May Be Important as a Mechanism of Improvement of Cardiac Function and Remodeling by Postinfarction Granulocyte Colony–Stimulating Factor Treatment
From the Second Department of Internal Medicine, Gifu University School of Medicine, Gifu (S.M., G.T., X.-H.C., N.W., Y.U., M.K., M.A., Y.M., C.L., K.S., H.F.); the Department of Cardiovascular Regeneration, Gifu University School of Medicine, Gifu (K.G., T.T., K.K.); and Kyoto Women’s University, Kyoto (A.K., T.F.), Japan.
Correspondence to Hisayoshi Fujiwara, MD, Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa Machi, Gifu 500-8705, Japan. E-mail gifuim-gif{at}umin.ac.jp
Received September 2, 2003; de novo received December 5, 2003; accepted February 20, 2004.
Background— We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony–stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration.
Methods and Results— In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 µg · kg–1 · d–1 of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5*, 0/0, and 0/0 mm2 · slice–1 · kg–1, granulation areas 0/0, 4.0±0.7/8.5±1.0*, 3.9±0.8/5.7±0.7,* and 0/0 mm2 · slice–1 · kg–1, and scar areas 0/0, 0/0, 0/0, and 4.2±0.5/7.9±0.9* mm2 · slice–1 · kg–1 in G and S, respectively (*P<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, surviving myocardial tissue areas within the risk areas were significantly increased in G despite there being no difference in LV weight, LV wall area, or cardiomyocyte size between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive 3,3,3',3'-tetramethylindocarbocyanine perchlorate and positive troponin I in G, suggesting enhanced myocardial regeneration by G.
Conclusions— The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.
Key Words: myocytes • ischemia • reperfusion • matrix metalloproteinase
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