Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure

Li, Yiwen; Takemura, Genzou; Okada, Hideshi; Miyata, Shusaku; Esaki, Masayasu; Maruyama, Rumi; Kanamori, Hiromitsu; Li, Longhu; Oginö, Kazuhíde; Yu, Ming; Khai, Ngin Cin; Mikami, Atsushi; Minatoguchi, Shinya; Fujiwara, Takako; Fujiwara, Hisayoshi

doi:10.1038/labinvest.3700367

Cited by 51 publications

(55 citation statements)

References 50 publications

(75 reference statements)

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“…We recently showed that G-CSF improved cardiac function of the mouse heart with a large old MI. 21 In that model, G-CSF-induced molecular signaling downstream of G-CSFR differed substantially from that seen in the present model despite the animal species used was same. Stat and Akt activation was augmented in the mouse heart with old MI, which was furthermore strengthened by G-CSF, whereas ERK activation was not influenced by G-CSF.…”

Section: Discussion G-csf Exerts a Protective Effect Against Dox-indumentioning

confidence: 40%

“…14, 21 We also found that DOX significantly downregulated myocardial G-CSFR expression and that this inhibitory effect was completely blocked by G-CSF. The mechanism by which DOX downregulates G-CSFR expression is entirely unknown, though DOX reportedly inhibits calcium-independent phospholipase A 2 .…”

Section: Discussion G-csf Exerts a Protective Effect Against Dox-indumentioning

confidence: 63%

“…21 After cardiac echocardiography, the right carotid artery was cannulated with a micromanometertipped catheter (SPR 671; Millar Instruments) and advanced into the aorta and then into the left ventricle (LV) for recording pressure and 7dP/dt.…”

Section: Physiological Studiesmentioning

confidence: 99%

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Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Takemura

et al. 2007

Laboratory Investigation

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It is not well-known yet how granulocyte colony-stimulating factor (G-CSF) affects nonischemic cardiomyopathy, though its beneficial effects on acute myocardial infarction are well-established. We hypothesize that G-CSF beneficially might affect nonischemic cardiomyopathy through the direct cardioprotective effects. Here, we show that a single injection of doxorubicin (DOX, 15 mg/kg) induced left ventricular dilatation and dysfunction in mice within 2 weeks, and that these effects were significantly attenuated by human recombinant G-CSF (100 mg/kg/day for 5 days). G-CSF also protected hearts against DOX-induced cardiomyocyte atrophy/degeneration, fibrosis, inflammatory cell infiltration and down regulation of GATA-4 and sarcomeric proteins, myosin heavy chain, troponin I and desmin, both in vivo and in vitro. Cardiac cyclooxygenase-2 was upregulated and G-CSF receptor was downregulated in DOX-induced cardiomyopathy, but both of those effects were largely reversed by G-CSF. No DOX-induced apoptotic effects were seen, nor were there any changes in tumor necrosis factor-a or transforming growth factor-b1 levels. Among downstream mediators of G-CSF receptor signaling, DOX-induced cardiomyopathy involved inactivation of extracellular signal-regulated protein kinase (ERK); the ERK inactivation was reversed by G-CSF. Inhibition of ERK activation, but not cyclooxygenase-2 inhibition, completely abolished beneficial effect of G-CSF on cardiac function. G-CSF did not promote differentiation of bone marrow cells into cardiomyocytes according to the experiment using green fluorescent protein-chimeric mice, and inhibition of CXCR4 þ cell homing using AMD3100 did not diminish the effect of G-CSF. Finally, G-CSF was also effective when administered after cardiomyopathy was established. In conclusion, these findings imply the therapeutic usefulness of G-CSF mainly through restoring ERK activation against DOX-induced nonischemic cardiomyopathy.

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Section: Discussion G-csf Exerts a Protective Effect Against Dox-indumentioning

confidence: 40%

Section: Discussion G-csf Exerts a Protective Effect Against Dox-indumentioning

confidence: 63%

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Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Takemura

et al. 2007

Laboratory Investigation

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“…Diverse pathological insults deplete GATA4 protein levels in the heart, including endotoxin (24), doxorubicin (36), and myocardial infarction (25). To identify alternative mechanisms to explain diabetic heart injury, we examined the effect of high glucose (HG) on expression of the cardiac-specific transcription/survival factor GATA4 in cultured NRVC.…”

Section: High Glucose Diminishes the Cardiac Transcription/survivalmentioning

confidence: 99%

“…As a survival factor, GATA4 contributes to cytoprotection in cardiomyocytes induced by endothelin-1 (21) and ischemic preconditioning (22,23). GATA-4 is markedly reduced in endotoxin or * This work was supported in part by Grant P20 RR-017662 (Project 3) from infarction-induced failing hearts, and treatments that improve cardiac function also restore GATA4 levels (24,25). Moreover, the anticancer drug doxorubicin depletes GATA4 protein levels and induces apoptosis in cardiomyocytes, which is prevented by overexpression of GATA4 (26).…”

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confidence: 99%

Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury

Kobayashi

Mao

Zheng

et al. 2007

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemiainduced cardiac damage remain poorly understood. The transcription factor GATA4 is essential for cardiac homeostasis, and its protein levels are dramatically reduced in the heart in response to diverse pathologic stresses. In this study, we investigated if hyperglycemia affects GATA4 expression in cardiomyocytes and if enhancing GATA4 signaling could attenuate hyperglycemia-induced cardiomyocyte injury. In cultured rat cardiomyocytes, high glucose (HG, 25 or 40 mM) markedly reduced GATA4 protein levels as compared with normal glucose (NG, 5.5 mM). Equal amount of mannitol did not affect GATA4 protein expression (NG, 100 ؎ 12%; mannitol, 97 ؎ 8%, versus HG, 43 ؎ 16%, p < 0.05). The GATA4 mRNA content, either steady-state or polysome-associated, remained unchanged. HG-induced GATA4 reduction was reversed by MG262, a specific proteasome inhibitor. HG did not activate the ubiquitin proteasome system (UPS) in cardiomyocytes as indicated by a UPS reporter, nor did it increase the peptidase activities or protein expression of the proteasomal subunits. However, the mRNA levels of ubiquitin-protein isopeptide ligase (E3) carboxyl terminus of Hsp70-interacting protein (CHIP) were markedly increased in HG-treated cardiomyocytes. CHIP overexpression promoted GATA4 protein degradation, whereas small interfering RNA-mediated CHIP knockdown prevented HG-induced GATA4 depletion. Moreover, overexpression of GATA4 blocked HG-induced cardiomyocyte death. Also, GATA4 protein levels were diminished in the hearts of streptozotocin and db/db diabetic mice (44 ؎ 7% and 67 ؎ 13% of control, p < 0.05), which correlated with increased CHIP mRNA abundance. In summary, increased GATA4 protein degradation may be an important mechanism that contributes to hyperglycemic cardiotoxicity.Diabetes is a major risk factor for the development of various cardiovascular diseases, including atherosclerosis, hypertension, and diabetic cardiomyopathy, which collectively constitute the leading causes of mortality from diabetes. Diabetic cardiomyopathy, independent of vascular pathology, is now recognized as an important causative factor for the heightened risk of heart failure and mortality in diabetic patients (1, 2). The characteristic metabolic abnormalities of diabetes include hyperlipidemia, hyperinsulinemia (type 2 diabetes), and hyperglycemia. The development of diabetic cardiomyopathy correlates with the duration and severity of hyperglycemia. Hyperglycemia induces cardiac damage through a number of biochemical mechanisms, including the formation of advanced glycation end products (3), altered calcium homeostasis (4), enhanced renin-angiotensin system (5), and protein kinase C activation (6). Ultimately, it is thought that hyperglycemia increases oxidative stress inducing cardiomyocyte death leading to heart failure in animals (7, 8) and humans (9) with diabetes. In fact, high concentrations of glucose induce the generation of r...

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G-CSF-Induced Mobilization of Bone Marrow Stem Cells and Cardiac Repair

Dawn

Sanganalmath

Bolli

2011

Twenty Years of G-CSF

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Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure

Cited by 51 publications

References 50 publications

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury

G-CSF-Induced Mobilization of Bone Marrow Stem Cells and Cardiac Repair

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