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G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes

Nature Medicine volume 11, pages 305–311 (2005)Cite this article

Abstract

Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.

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Figure 1: Expression of G-CSFR and the G-CSF-evoked signal transduction in cultured cardiomyocytes.
Figure 2: Suppression of H2O2-induced cardiomyocyte apoptosis by G-CSF.
Figure 3: Effects of G-CSF on cardiac function after myocardial infarction.
Figure 4: Mechanisms of the protective effects of G-CSF.
Figure 5: Direct effects of G-CSF on cardiac function after ischemia-reperfusion injury.

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Acknowledgements

The authors thank J. Robbins (Children's Hospital Research Foundation, Cincinnati, Ohio) for a fragment of the αMHC gene promoter, M. Tamagawa for the analysis of Langendorff-perfused model, Kirin Brewery Co., Ltd. for their kind gift of G-CSF, and M. Watanabe and E. Fujita for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research, Developmental Scientific Research, and Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Drug ADR Relief, R&D Promotion and Product Review of Japan (to I.K.) and Japan Research Foundation for Clinical Pharmacology (to T.M.).

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Author notes

  1. Mutsuo Harada, Yingjie Qin, Hiroyuki Takano and Tohru Minamino: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Mutsuo Harada, Yingjie Qin, Hiroyuki Takano, Tohru Minamino, Yunzeng Zou, Haruhiro Toko, Masashi Ohtsuka, Katsuhisa Matsuura, Masanori Sano, Jun-ichiro Nishi, Koji Iwanaga, Hiroshi Akazawa, Takeshige Kunieda, Weidong Zhu, Hiroshi Hasegawa, Toshio Nagai & Issei Komuro

  2. Department of Molecular Medicine, Osaka University Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Keita Kunisada & Keiko Yamauchi-Takihara

  3. Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Haruaki Nakaya

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Correspondence to Issei Komuro.

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Supplementary information

Supplementary Fig. 1

Immunocytochemical staining for G-csfr. (PDF 76 kb)

Supplementary Fig. 2

RT-PCR for the mouse G-csfr. (PDF 33 kb)

Supplementary Fig. 3

Effects of AG490 on basal expression of Bcl-2. (PDF 17 kb)

Supplementary Fig. 4

Western blot for G-csfr. (PDF 25 kb)

Supplementary Fig. 5

Effects of G-CSF on the MI heart. (PDF 18 kb)

Supplementary Fig. 6

Effects of AG490 on the G-CSF treatment. (PDF 13 kb)

Supplementary Fig. 7

Expression of Bcl-2. (PDF 86 kb)

Supplementary Fig. 8

Effects of G-CSF on cardiac homing of the bone marrow cells. (PDF 12 kb)

Supplementary Fig. 9

Effects of G-CSF on cardiac stem cells. (PDF 12 kb)

Supplementary Fig. 10

Number of cardiomyocytes in G1-S stages of cell cycle. (PDF 74 kb)

Supplementary Fig. 11

Initial area sizes at risk. (PDF 10 kb)

Supplementary Fig. 12

Initial infarct size. (PDF 10 kb)

Supplementary Methods (PDF 39 kb)

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Harada, M., Qin, Y., Takano, H. et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11, 305–311 (2005). https://doi.org/10.1038/nm1199

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