title: G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes.
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.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harada
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Matsuura
authors.forename: Masanori
authors.initials: M
authors.lastname: Sano
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Nishi
authors.forename: Koji
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Takeshige
authors.initials: T
authors.lastname: Kunieda
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Keita
authors.initials: K
authors.lastname: Kunisada
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004789:Enzyme Activation; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019650:Hematopoietic Stem Cell Mobilization; D053614:Janus Kinase 2; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051381:Rats; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis; D016276:Ventricular Function / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2