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Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction¹

Kotaro Naito^*, Toshihisa Anzai^2,*, Yasuo Sugano^*, Yuichiro Maekawa^*, Takashi Kohno^*, Tsutomu Yoshikawa^*, Kenjiro Matsuno and Satoshi Ogawa^*

^* Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; and Department of Anatomy (Macro) and Solution-Oriented Research for Science and Technology (SORST), Dokkyo University School of Medicine, Tochigi, Japan

Several lines of evidence suggest that the immune activation after myocardial infarction (MI) induces secondary myocardial injury. Although dendritic cells (DC) are potent regulators of immunity, their role in MI is still undetermined. We investigated the effect of DC modulation by CSF on left ventricular (LV) remodeling after MI. MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 µg/kg/day, MI-G, n = 33), a GM-CSF inducer (romurtide, 200 µg/kg/day, MI-GM, n = 28), or saline (MI-C, n = 55) was administered for 7 days. On day 14, MI-G animals had higher LV max dP/dt and smaller LV dimensions, whereas MI-GM animals had lower LV max dP/dt and larger LV dimensions than did MI-C animals, despite similar infarct size. In MI-C, OX62⁺ DC infiltrated the infarcted and border areas, peaking on day 7. Bromodeoxyuridine-positive DC were observed in the border area during convalescence. Infiltration by DC was decreased in MI-G animals and increased in MI-GM animals compared with MI-C (p < 0.05). In the infarcted area, the heat shock protein 70, TLR2 and TLR4, and IFN- expression were reduced in MI-G, but increased in MI-GM in comparison with those in MI-C animals. IL-10 expression was higher in MI-G and lower in MI-GM than in MI-C animals. In conclusion, G-CSF improves and GM-CSF exacerbates early postinfarction LV remodeling in association with modulation of DC infiltration. Suppression of DC-mediated immunity could be a new strategy for the treatment of LV remodeling after MI.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Keio University Medical School Faculty and Alumni Grant (to T.A.) and by grants for scientific research 18790511 (to K.N.) and 16790433 (to Y.S.) from the Japan Ministry of Education, Culture, Sports, Science and Technology.

² Address correspondence and reprint requests to Dr. Toshihisa Anzai, Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: anzai{at}cpnet.med.keio.ac.jp

³ Abbreviations used in this paper: LV, left ventricle; ALP, alkaline phosphatase; DC, dendritic cells; HSP, heat shock protein; MI, myocardial infarction.