Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis

Kitta, Kazumi; Day, Regina M.; Ikeda, Takayuki; Suzuki, Yuichiro

doi:10.1016/s0891-5849(01)00663-3

Cited by 94 publications

(81 citation statements)

References 33 publications

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“…Recent findings suggest that apoptosis among cardiomyocytes is a leading cause of cardiac dysfunction in doxorubicininduced cardiomyopathy (13,36). This hypothesis remains controversial, however, because the cardiomyocytes in question do not show the typical apoptotic morphology (16,17,30,38).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, HGF also reportedly exhibits cardioprotective effects. For instance, HGF protected cardiomyocytes from acute ischemic death during myocardial infarction (27,36), and it enhanced survival among cardiomyocytes subjected to oxidative stress (13,36). In addition to its beneficial effects on cardiomyocytes under acute stress, recent research has demonstrated that HGF also exerts beneficial effects on cardiac function in animal models of chronic heart diseases, including ischemic cardiomyopathy following old myocardial infarction and hereditary cardiomyopathy (18,28,34).…”

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confidence: 99%

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Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Esaki

Takemura²,

Kosai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Hepatocyte growth factor (HGF) reportedly exerts beneficial effects on the heart following myocardial infarction and during nonischemic cardiomyopathy, but the precise mechanisms underlying the latter have not been well elucidated. We generated nonischemic cardiomyopathy in mice by injecting them with doxorubicin (15 mg/kg ip). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1×1011 particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 wk after doxorubicin administration were significantly mitigated in HGF-treated mice, as were the associated cardiomyocyte atrophy/degeneration and myocardial fibrosis. Myocardial expression of GATA-4 and a sarcomeric protein, myosin heavy chain, was downregulated by doxorubicin, but the expression of both was restored by HGF treatment. The protective effect of HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation plays significant roles in the present model. Upregulation of c-Met/HGF receptor was noted in HGF-treated hearts. Among the mediators downstream of c-Met, the activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-β1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest the HGF gene delivery exerts therapeutic antiatrophic/degenerative and antifibrotic effects on myocardium in cases of established cardiac dysfunction caused by doxorubicin. These beneficial effects appear to be related to HGF-induced ERK activation and upregulation of c-Met, GATA-4, and sarcomeric proteins.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Esaki

Takemura²,

Kosai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…3,4 Recent studies, however, reported cardioprotective effects of HGF: HGF protected cardiomyocytes from acute ischemic death during acute myocardial infarction (MI) 5,6 and enhanced survival of cardiomyocytes subjected to oxidant stress. 6,7 These studies focused on the effects of HGF on cardiomyocytes under acute stress.…”

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confidence: 99%

Postinfarction Treatment With an Adenoviral Vector Expressing Hepatocyte Growth Factor Relieves Chronic Left Ventricular Remodeling and Dysfunction in Mice

et al. 2003

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Background-Hepatocyte growth factor (HGF) is implicated in tissue regeneration, angiogenesis, and antiapoptosis.However, its chronic effects are undetermined on postinfarction left ventricular (LV) remodeling and heart failure. Methods and Results-In mice, on day 3 after myocardial infarction (MI), adenovirus encoding human HGF (Ad.CAG-HGF) was injected into the hindlimb muscles (nϭ13). As a control (nϭ15), LacZ gene was used. A persistent increase in plasma human HGF was confirmed in the treated mice: 1.0Ϯ0.2 ng/mL 4 weeks later. At 4 weeks after MI, the HGF-treated mice showed improved LV remodeling and dysfunction compared with controls, as indicated by the smaller LV cavity and heart/body weight ratio, greater % fractional shortening and LV ϮdP/dt, and lower LV end-diastolic pressure. The cardiomyocytes near MI, including the papillary muscles and trabeculae, were greatly hypertrophied in the treated mice. The old infarct size was similar between the groups, but the infarct wall was thicker in the treated mice, where the density of noncardiomyocyte cells, including vessels, was greater. Fibrosis of the ventricular wall was significantly reduced in them. Examination of 10-day-old MI revealed no proliferation or apoptosis but showed augmented expression of c-Met/HGF receptor in cardiomyocytes near MI, whereas a greater proliferating activity and smaller apoptotic rate of granulation tissue cells in the HGF-treated hearts was observed compared with controls. Conclusions-Postinfarction HGF gene therapy improved LV remodeling and dysfunction through hypertrophy of cardiomyocytes, infarct wall thickening, preservation of vessels, and antifibrosis. These findings imply a novel therapeutic approach against postinfarction heart failure.

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“…In the bleomycin-induced lung injury model in rats (11), HGF showed the proliferative effect on type II alveolar epithelial cells, but showed the antiproliferative effect on alveolar macrophages and fibroblasts mainly implicated in the occurrence of fibrotic changes of the lung. In addition, it has recently been shown that endogenous and exogenous HGF protects cardiac myocytes in a rat model of ischemia/reperfusion injury (12) and that the addition of HGF in the culture effectively protects adult rat cardiac myocytes from oxidative stress-induced apoptosis (13). Thus, it is speculated that HGF might play a role in the physiologic repair process of respiratory epithelium after acute and chronic lung injuries.…”

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confidence: 99%

Hepatocyte Growth Factor Protects Small Airway Epithelial Cells from Apoptosis Induced by Tumor Necrosis Factor-α or Oxidative Stress

et al. 2004

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Involvement of hepatocyte growth factor (HGF) in lung morphogenesis and regeneration has been established by in vitro and in vivo experiments in animals. In the present study, the protective activity of HGF against tumor necrosis factor (TNF)-␣ or hydrogen peroxide (H 2 O 2 )-induced damage of pulmonary epithelial cells was examined using the human small airway epithelial cell line (SAEC). Western blot analysis revealed that the receptor for HGF (c-Met) was highly expressed on the surface of SAEC and its downstream signal transduction pathway was functional. The SAEC was induced into apoptosis by the treatment with TNF-␣ or H 2 O 2 in a dose-dependant manner, but was significantly rescued from apoptosis in the presence of HGF. The HGF effect was evident when added not only at the same time but also within several hours after treatment. This protective activity of HGF against the TNF-␣-or H 2 O 2 -induced apoptosis was mediated, at least in part, by up-regulating the nuclear factor B activity and an increase in the ratio of apoptosis-suppressing to apoptosis-inducing proteins. These results suggest that administration of HGF might exhibit a potent function in vivo for protection and improvement of acute and chronic lung injuries induced by inflammation and/or oxidative stress. Lung development and morphogenesis begin in the fetal period of embryo and finally reach the formation of mature alveolar cells around 36 wk of gestation. The control of lung development is complicated and known to be influenced by the interaction between pulmonary epithelial and mesenchymal cells, which is mainly mediated by autocrine and paracrine mechanisms via a variety of polypeptides expressed on or secreted from mesenchymal cells (1).HGF, which was originally purified and cloned as a potent mitogen for mature hepatocytes in primary culture (2-4), is a cytokine mainly produced by cells of mesenchymal origin (5). Previous studies have demonstrated that HGF has multifunctional activities such as mitogenic, morphogenic, and motogenic on a variety of epithelial cells (5, 6), including pulmonary epithelial cells (7). Pulmonary mesenchymal cells synthesize and secrete HGF, which has been shown to be involved not only in the formation of bronchoalveolar structure during fetal development, but also in the repair process of injured distal organs such as liver and kidney (7-10). In the bleomycin-induced lung injury model in rats (11), HGF showed the proliferative effect on type II alveolar epithelial cells, but showed the antiproliferative effect on alveolar macrophages and fibroblasts mainly implicated in the occurrence of fibrotic changes of the lung. In addition, it has recently been shown that endogenous and exogenous HGF protects cardiac myocytes in a rat model of ischemia/reperfusion injury (12) and that the addition of HGF in the culture effectively protects adult rat cardiac myocytes from oxidative stress-induced apoptosis (13). Thus, it is speculated that HGF might play a role in the physiologic repair process of respiratory epithelium...

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Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis

Cited by 94 publications

References 33 publications

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Postinfarction Treatment With an Adenoviral Vector Expressing Hepatocyte Growth Factor Relieves Chronic Left Ventricular Remodeling and Dysfunction in Mice

Hepatocyte Growth Factor Protects Small Airway Epithelial Cells from Apoptosis Induced by Tumor Necrosis Factor-α or Oxidative Stress

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