Effects Of Hepatocyte Growth Factor Research Articles

Inhibitory Effects of Hepatocyte Growth Factor and Interleukin-6 on Transforming Growth Factor-β1 Mediated Vocal Fold Fibroblast-Myofibroblast Differentiation

The role of myofibroblasts in vocal fold scarring has not been extensively studied, partly because of the lack of a robust in vitro model. The objective of this investigation was to develop and characterize a myofibroblast in vitro model that could be utilized to investigate the molecular mechanism of myofibroblast differentiation and function in injured vocal fold tissue. Differentiation of human primary vocal fold fibroblasts (hVFFs) to myofibroblasts was stimulated with 5, 10, or 20 ng/mL of recombinant transforming growth factor-beta1 (TGF-beta1). Cultures were analyzed by immunofluorescence and Western blotting, with an alpha-smooth muscle actin (alpha-SMA) antibody used as a myofibroblast marker. Normal rabbit vocal folds were treated with 10 ng/mL of TGF-beta1 for 7 days for in vivo corroboration. The effects of interleukin-6 (IL-6) and hepatocyte growth factor (HGF) on myofibroblast differentiation were studied with Western blots. The hVFFs demonstrated positive alpha-SMA labeling in cells stimulated by 10 and 20 ng/mL TGF-beta1, indicating that hVFFs were capable of differentiation to myofibroblasts. Transforming growth factor-beta1 induced the largest increase in alpha-SMA at 10 ng/mL on day 5 of treatment. Both HGF and IL-6 suppressed the expression of TGF-beta1-induced alpha-SMA. Our work characterizes a useful in vitro model of TGF-beta1-mediated vocal fold fibroblast-myofibroblast differentiation. The extent of differentiation appears to be attenuated by HGF, suggesting a potential mechanism to support prior work indicating that HGF plays a protective role in reducing scar formation in vocal fold injuries. Paradoxically, IL-6, which has been shown to play a profibrotic role in dermal studies, also attenuated the TGF-beta1 response.

IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway

Excessive accumulation of collagen contributes to the fibrotic process. Several experimental studies have shown that IFN-gamma is effective in preventing fibrogenesis. IL-18, originally identified as an IFN-gamma-inducing factor, is a key mediator of inflammation and host defense responses. In this study, we investigated the regulatory effect of IL-18 on the expression of type I and III collagen genes in dermal fibroblasts. The exposure of human dermal fibroblasts (HDFs) to IL-18 resulted in a reduction of collagen gene expression and production. Also, IL-18 inhibited the fibrogenic cytokine transforming growth factor (TGF)-beta-induced collagen gene expression. Next, to determine the molecular mechanism involved in this regulation, we showed that IL-18-regulated collagen expression was blocked by small interfering RNA (siRNA)-mediated Ets-1 knockdown. Furthermore, we showed that IL-18 induced phosphorylation of extracellular signal-regulated kinase (ERK) within 10 minutes and that the ERK inhibitor PD98059 blocked the inhibitory effect of IL-18. IL-18 also inhibited the production of collagen in systemic sclerosis (SSc) dermal fibroblasts. Our data indicate that IL-18 downregulates collagen production in HDF directly via Ets-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts.

Novel Proapoptotic Effect of Hepatocyte Growth Factor: Synergy with Palmitate to Cause Pancreatic β-Cell Apoptosis

Increasing evidence suggests that elevation of plasma fatty acids that often accompanies insulin resistance contributes to beta-cell insufficiency in obesity-related type 2 diabetes. Circulating levels of hepatocyte growth factor (HGF) are increased in humans with metabolic syndrome and obesity. HGF is known to protect beta-cells against streptozotocin and during islet engraftment. However, whether HGF is a beta-cell prosurvival factor in situations of excessive lipid supply has not been deciphered. Mice overexpressing HGF in the beta-cell [rat insulin type II promoter (RIP)-HGF transgenic mice] fed with standard chow display improved glucose homeostasis and increased beta-cell mass and proliferation compared with normal littermates. However, after 15 wk of high-fat feeding, glucose homeostasis and beta-cell expansion and proliferation are indistinguishable between normal and transgenic mice. Interestingly, RIP-HGF transgenic mouse beta-cells and normal beta-cells treated with HGF display increased sensitivity to palmitate-mediated apoptosis in vitro. Palmitate completely eliminates Akt and Bad phosphorylation in RIP-HGF transgenic mouse islets. HGF-overexpressing islets also show significantly decreased AMP-activated protein kinase-alpha and acetyl-coenzyme A carboxylase phosphorylation, diminished fatty acid oxidation, increased serine palmitoyltransferase expression, and enhanced ceramide formation compared with normal islets. Importantly, human islets overexpressing HGF also display increased beta-cell apoptosis in the presence of palmitate. Treatment of both mouse and human islet cells with the de novo ceramide synthesis inhibitors myriocin and fumonisin B1 abrogates beta-cell apoptosis induced by HGF and palmitate. Collectively, these studies indicate that HGF can be detrimental for beta-cell survival in an environment with excessive fatty acid supply.

Facilitated Tendon-Bone Healing by Local Delivery of Recombinant Hepatocyte Growth Factor in Rabbits

This study was performed to evaluate the therapeutic effect of hepatocyte growth factor (HGF) on tendon-bone healing in a rabbit model. In adult rabbits the long digital extensor tendon was detached from the lateral femoral condyle, and the free end of the tendon was inserted into a tunnel drilled into the proximal tibial metaphysis. Cancellous bone obtained during drilling of the tibial hole was soaked in saline solution or solution containing 100-microg/mL human recombinant HGF and then transplanted into the bone tunnel. Junctional healing between the tendon and the bone was evaluated by histologic analysis and uniaxial load-to-failure testing at 2, 4, 6, 8, and 12 weeks after surgery. In the saline solution-treated control group, Sharpey-like fibers, which connected the tendon graft and the bone tissue, appeared 6 weeks after treatment. At 8 weeks after treatment, maturation of lamellar bone was seen, and at 12 weeks, the adhesion between tendon and bone appeared to be supported by indirect insertion of fibrocartilaginous tissue, wherein the border between the fibrocartilaginous tissue and tendon or bone was significant. In the HGF-treated group, the fibrous tissues were parallel to the load axis, and lamellar bone and Sharpey-like fibers appeared as early as 4 weeks after treatment. At 12 weeks, junctional tissue, characterized by a continuous 4-layer structure of bone, calcified cartilage, fibrocartilage, and tendon, was regenerated by a direct insertion. On biomechanical testing, the HGF-treated group had significantly better biomechanical properties than the control group at 2 and 4 weeks. The histologic improvement caused by HGF treatment was associated with the biomechanical improvement. Local administration of recombinant HGF promotes the adhesive healing process at the tendon-bone junction, both histologically and mechanically, after ligament reconstruction in a rabbit model. Application of HGF may be considered as a new therapeutic approach to accelerate healing and rehabilitation after ligament reconstruction.

Relevance of Hepatocyte Growth Factor and Fibroblast Growth Factor on Mouse Preimplantation Embryo Development

Objective To explore the effect of hepatocyte growth factor (HGF) and fibroblast growth factor (FGF) on preimplantation embryo development of mouse. Methods Mated mice were killed by cervical dislocation to collect two pronucleous (2 PN) zygotes from oviduct of pregnant 1 d NMRI mice and were cultured to the hatching blastocyst stage and the number of embryo in different stages was recorded under an invert microscope. The cleavage rates of formed 2 PN zygotes were compared with blastocyst and hatching blastocyst stage in drops of T6 medium with or without HGF or FGF (0 ng/ml, 10 ng/ml, 20 ng/ml, 50 ng/ml, 1 000 ng/ml). Results HGF and FGF enriched embryo culture media promoted the development from 2 PN stage embryos to blastocyst. Adding 20 ng/ml of FGF or HGF to the culture medium significantly increased the percentage of 2PN embryos that developed into blastocysts (P Conclusion Exogenous HGF and FGF at low concentrations promote in-vitro mouse blastocyst formation.

Pathology and Strategies for the Treatment of Ischemic Brain Injury

Cerebral ischemia, a pathological condition in which brain tissue experiences a shortage or lack of glucose and oxygen, provokes an irreversible neurodegenerative disorder that may lead clinically to a progressive dementia and global cognitive deterioration. Accumulating evidence indicates many biochemical cascades that lead ultimately to ischemia-induced cell death. However, the cellular and molecular aspects of cerebral ischemia are not yet fully understood. Since the pattern of pathophysiological alterations is not the same for all cells in the ischemic brain, a good understanding of the cellular and molecular alterations induced by cerebral ischemia is needed to develop strategies for the treatment of stroke. This review summarizes recent advances concerning the pathophysiological alterations caused by cerebral ischemia, focusing on the modification of properties of glutamate receptors, which modification may be linked to the development of cerebral infarction. Furthermore, the effects of hepatocyte growth factor on learning dysfunction and cerebral vessel injury after cerebral ischemia are also summarized. Finally, this review describes a possible ameliorative effect of the injection of exogenous neural progenitor cells on cerebral ischemia-induced learning and memory dysfunction.

Hepatocyte growth factor protects auditory hair cells from aminoglycosides

To examine the effect of hepatocyte growth factor (HGF) for protection of auditory hair cells against aminoglycosides and its molecular mechanisms. Experimental study. We quantitatively assessed protective effects of HGF on mouse cochlear hair cells against neomycin toxicity using explant culture systems. To understand mechanisms of hair cell protection by HGF, we examined the expression of c-Met, HGF receptor, and 4-hydroxynonenal (a lipid peroxidation marker) in the cochlea by means of immunohistochemistry and Western blotting. The application of HGF to cochlear explant cultures significantly reduced the hair cell loss induced by neomycin. Immunohistochemistry showed c-Met expression in normal auditory hair cells, and its increase in response to neomycin-induced damage. Immunostaining for 4-hydroxynonenal suggested that HGF acted by attenuating the lipid peroxidation of auditory epithelia induced by neomycin. These findings demonstrate that a functional HGF/c-Met coupling is present in the cochlea, and HGF application exerts protective effects on hair cells, indicating the potential of HGF as a therapeutic agent for sensorineural hearing loss.

HEPATOCYTE GROWTH FACTOR PLAYS A CRITICAL ROLE IN THE REGULATION OF CYTOKINE PRODUCTION AND INDUCTION OF ENDOTHELIAL PROGENITOR CELL MOBILIZATION: A PILOT GENE THERAPY STUDY IN PATIENTS WITH CORONARY HEART DISEASE

1. There is growing evidence of the beneficial effects of hepatocyte growth factor (HGF) in myocardial infarction, heart failure and occlusive peripheral arterial disease. The aim of the present study was to evaluate the effects of intracoronary administration of an adenovirus vector encoding the human HGF gene (Ad-HGF) on serum levels of cytokines and mobilization of CD34(+) and CD117(+) cells in patients with coronary heart disease. 2. Twenty-one patients with severe coronary artery disease were recruited to the study: 11 patients received both a stent and administration of Ad-HGF; the remaining 10 patients received a stent alone and served as the control group. Blood samples were obtained from the femoral vein before and then 6 and 24 h, 3 and 6 days and 2 weeks after treatment for the isolation of serum and peripheral blood mononuclear cells. Intracoronary administration of Ad-HGF in patients with coronary heart disease resulted in high levels of HGF gene expression, as well as its receptor c-met, compared with the control group, as demonstrated by real-time reverse transcription-polymerase chain reaction. In addition, serum levels of HGF, vascular endothelial growth factor, monocyte chemoattractant protein-1 and interleukin (IL)-10 were increased and serum levels of IL-8 were decreased in patients administered Ad-HGF compared with the control group. The percentage of CD34(+) and CD117(+) cells in the peripheral blood increased in patients administered Ad-HGF. 3. In conclusion, HGF gene therapy may play an important role in the regulation of cytokines and the induction of endothelial progenitor cell mobilization in patients with coronary heart disease.

The effects of hepatocyte growth factor and insulin‐like growth factor‐1 on the myogenic differentiation of satellite cells in human urethral rhabdosphincter

To examine the effects of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) on the myogenic differentiation of human urethral rhabdosphincter (RS) satellite cells. Human RS was obtained from patients undergoing radical prostatectomy for prostate cancer. Selectively cultured RS satellite cells, transfected with temperature sensitive simian virus-40 T antigen (ts-SV40 Tag) to extend their lifespan, were cultured at 33 degrees C, and then incubated at 39 degrees C to induce myogenic differentiation. Varying concentrations of HGF and IGF-1 were added to the differentiation medium. Inactivation of SV40 Tag and evaluations of myogenic differentiation were examined by immunocytochemistry, western blotting and real-time RT-PCR. At 39 degrees C, ts-SV40 Tag-transfected RS satellite cells slowly proliferated, fused to form multinucleated myotubes, and expressed myosin heavy chain (MHC) in association with the temperature-dependent inactivation of SV40 Tag. IGF-1 significantly accelerated the MHC expression in a dose-dependent fashion through activation of the PI3-kinase pathway. Conversely, HGF did not promote MHC expression due a reduction in phosphorylation of both the MAP-kinase and the PI3-kinase pathways, a pattern of response different than the response of proliferating RS satellite cells to HGF. HGF did not induce myogenic differentiation of RS satellite cells. Conversely, IGF-1 promoted myogenic differentiation of RS satellite cells via the PI3-K pathway likewise proliferating RS satellite cells. These findings may be useful for developing novel techniques for regenerating the human RS to treat urinary incontinence.

Hepatocyte growth factor and epidermal growth factor promote spheroid formation in polyurethane foam/hepatocyte culture and improve expression and maintenance of albumin production

In our previous pre-clinical study with pig hepatic failure, an artificial liver with polyurethane foam (PUF)/primary porcine hepatocyte spheroids had superior curative effect. We examined the effect of hepatocyte growth factor (HGF), also known as scatter factor, on the quick formation of hepatocyte spheroids and albumin production. Spheroids were formed in the pores of PUF within 3 days regardless of addition of growth factors. In particular, spheroids were formed within 1 day in medium containing 100 ng/ml HGF and 50 ng/ml epidermal growth factor (EGF). 10,000 ng/ml HGF was effective for albumin production, but the activity dramatically decreased after 6 days in EGF-free medium. On the other hand, 100 ng/ml HGF was effective for albumin production in EGF-containing medium. Albumin production rate with ≥1000 ng/ml HGF was about 1.5 times higher than that with 100 ng/ml HGF. Furthermore, albumin production rate at 3 weeks was about 1.5 times higher than that at 2 days with 1000 ng/ml HGF. The maintenance of albumin production rate depended on the activity of the individual cell and not cell growth. In other words, we were able to show the effectiveness of HGF for functional hepatocyte organoid formation in PUF pores.

Generation of insulin-secreting cells from adult rat pancreatic ductal epithelial cells induced by hepatocyte growth factor and betacellulin-δ4

The present study was conducted to identify effective factors that could induce differentiation of pancreatic ductal epithelial cells (PDECs) into insulin-producing cells. We examined the effect of hepatocyte growth factor (HGF) and betacellulin-δ4 (BTC-δ4) on PDECs. We isolated PDECs from adult rats and stimulated them with HGF and BTC-δ4 for 28days. We observed several characteristics of PDECs after induction, including functional changes in PDECs, differentiation rate, and expression levels of critical transcription factors. We observed that insulin content and glucose-induced insulin secretion were significantly higher in induced PDECs compared to control PDECs. The expression of markers specific to mature β-cells, i.e., insulin and glucose transporter-2 (GLUT2) was also observed. An analysis of the expression of different transcription factors (PDX-1, Ngn3, NeuroD, and Pax4) revealed that cell-specific gene expression patterns varied from 7 to 28days after treatment. Hence, we conclude that treatment with a combination of HGF and BTC-δ4 is effective in inducing the differentiation of PDECs into insulin-secreting cells.

The antifibrogenic effect of hepatocyte growth factor (HGF) on renal tubular (HK-2) cells is dependent on cell growth

Although several reports suggest an antifibrogenic effect of hepatocyte growth factor (HGF), an increased deposition of matrix induced by HGF has also been reported. These conflicting effects could result from a diverse proliferative state of the target cells. Aim of the present study was to evaluate HGF effects on growth arrested (quiescent) and actively proliferating renal tubular epithelial (HK-2) cells.HK-2 cells were cultured in RPMI medium either on agarose gel or on plastic surface in order to inhibit or to allow cell proliferation. Cells were incubated with RPMI containing HGF (50 ng/ml) for 24 h at 37°C. Untreated HK-2 were used as control. After 24 h of incubation, cells were counted by Coulter counter. (α2)IV collagen, transforming growth factor-β (TGF-β), Tissue inhibitor of metalloproteases (TIMP1 and 2) mRNA levels were determined by RT-PCR. The production of type IV collagen, c-met, proliferating cell nuclear antigen (PCNA), and SnoN, a transcriptional Smad corepressor and thus a TGF-β inhibitor, was evaluated by ELISA or western blotting. MMP-9 and 2 gelatinolytic activity was studied by zymography.Treatment with HGF did not increase HK-2 cell number and PCNA synthesis when the cells were grown on agarose as it did for cells grown on plastic surface. HGF increased (α2)IV collagen in proliferating cells whereas it reduced (α2)IV collagen and c-met synthesis in growth arrested cells. HGF treatment increased TGF-β and TIMP-2 in proliferating cells while reduced TIMP-1 mRNA levels of quiescent cells. Furthermore, production of the co repressor SnoN was significantly decreased by HGF in proliferating cells. Quiescent and proliferating HK-2 showed a different pattern of metalloproteases activity with a prevalence of MMP2 in quiescent and MMP9 in proliferating cells. In summary, HGF showed opposite effects on growth arrested and proliferating HK-2 cells favouring matrix deposition in the latter with increasing expression of collagen, TIMP-1 and TGF-β. Our results demonstrate that the proliferative state of target cells may influence the effects of HGF on extracellular matrix turnover in HK-2 cells.

Effects of hepatocyte growth factor on the expression and phosphorylation of focal adhesion kinase in SMMC-7721 cells

Effects of hepatocyte growth factor on the expression and phosphorylation of focal adhesion kinase in SMMC-7721 cells

Reactive oxygen species regulate the generation of urokinase plasminogen activator in human hepatoma cells via MAPK pathways after treatment with hepatocyte growth factor

Tumor cells are known to produce larger amounts of reactive oxygen species (ROS) than normal cells. Although numerous reports have indicated the importance of ROS in urokinase plasminogen activator (uPA) production, the precise mechanisms remain controversial. In our study, we investigated the effect of ROS on uPA generation in human hepatoma cells, HepG2 and Hep 3B. We determined the effects of hepatocyte growth factor (HGF) on the regulation of ROS, which resulted in suppression of ROS production, as measured with the fluorescent probe, 2'-7'-dichlorofluorescein diacetate. The role of HGF in modulating ROS production, particularly that regulated by Rac-1, was determined. HGF suppressed the increment in Rac-1-regulated ROS in both cell lines. Treatment with 200 micrometer of H(2)O(2) showed a 1.6-2.1 fold increment in HGF, but a little increment occurred at 500 micrometer of H(2)O(2). It looks no dose dependent manner. Combined treatment with H(2)O(2) and HGF, resulted in a slightly increased production of HGF compared to no treatment (control). Also, H(2)O(2) upregulated uPA expression in both hepatoma cell lines. To identify the downstream pathways regulated by ROS, we treated cells with PD 98059, an MEK inhibitor, and SB 203580, a p38 inhibitor, after treatment with H(2)O(2), and showed negative control between ERK and p38 kinase activities for uPA regulation. We found that HGF modulate Rac-1-regulated ROS production through activation of Akt and ROS regulates uPA production via MAP kinase, which provides a novel clue to clarify the mechanism underlying hepatoma progression.

The effects of hepatocyte growth factor on phenotype of human retinal pigment epithelium cells

目的 探讨肝细胞生长因子(HGF)对人视网膜色素上皮(RPE)细胞形态及细胞表面抗原的影响.方法 体外培养人RPE细胞,分别采用0.4%小牛血清和重组人HGF因子刺激人RPE细胞,应用相差显微镜观察细胞形态变化;免疫组织化学方法 检测细胞表面抗原细胞角蛋白、波形蛋白、成纤维细胞特异性蛋白-1(Fsp-1)的表达变化;采集经HGF(20 ng/mL)刺激后0、12、24、48 h的RPE细胞应用RT-PCR方法 观察Fsp-1mRNA的表达变化.结果 体外培养的人RPE细胞,在含0.4%小牛血清培养液中呈多角形,贴壁生长融合后呈铺路石样;细胞角蛋白的表达阳性率为89.7%,波形蛋白阳性率为100%,Fsp-1阳性率为45.3%.HGF(20 ng/mL)刺激24 h后,细胞呈长梭形,具有成纤维细胞形态特征;细胞角蛋白阳性率为50.1%(χ2=38.1,P＜0.01),Fsp-1阳性率为91.2%(χ2=48.62,P＜0.01),而波形蛋白表达无明显变化.HGF作用后,Fsp-1mRNA表达升高(F=13.761,P=0.002). 结论 HGF促进人RPE细胞向成纤维细胞的表型转化,提示HGF在RPE细胞上皮-间质转化过程中起重要作用。

Letter by Kaneda Regarding Article, “Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden”

HomeCirculationVol. 118, No. 22Letter by Kaneda Regarding Article, “Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Kaneda Regarding Article, “Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden” Hideaki Kaneda, MD, PhD Hideaki KanedaHideaki Kaneda Okinaka Memorial Institute for Medical Research, Tokyo, Japan Search for more papers by this author Originally published25 Nov 2008https://doi.org/10.1161/CIRCULATIONAHA.108.803189Circulation. 2008;118:e706To the Editor:With great interest I read the article by Ballantyne et al examining whether rosuvastatin could regress coronary atherosclerosis by quantitative coronary angiography (QCA).1 First, the authors excluded 50 patients with adverse events and reported that 4 patients died and 10 patients (5 of whom had QCA analysis) suffered from myocardial infarction. Because these patients were likely to have progression of coronary stenoses, it would be of great help if the authors would provide additional results imputing noncompleters, as was done in the previous intravascular ultrasound (IVUS) study.2Second, as the authors blinded baseline and follow-up images, lesions with >25% stenosis either at baseline or follow-up were assumed to be measured. However, the authors included only lesions with >25% stenosis at baseline. Exclusion of the lesions with <25% at baseline but >25% at follow-up may lead to underestimation of disease progression. In addition, the authors stated that “another limitation is the dropout rate of 25%; however, this rate is comparable to the dropout rate in similar populations in recent IVUS studies… and in prior QCA studies.” However, only 292 patients out of 507 (58%) receiving at least 1 dose of study drug were included in this study.Third, the authors demonstrated association of effects on low-density lipoprotein cholesterol with measures of stenosis by QCA between several trials of statin therapy. However, because a low-density lipoprotein cholesterol goal of <70 mg/dL was achieved in few patients in previous studies, to examine the impact of low-density lipoprotein cholesterol levels (<70 mg/dL) on QCA variables, it seems appropriate to provide regression analysis within this study (low-density lipoprotein cholesterol versus QCA variables in individual patients), even though no significant correlations were found between the on-therapy lipid levels and changes in the QCA parameters.3Fourth, in the Discussion section, the authors stated, “We show that 2 imaging modalities, which clearly measure different parameters and focus on different segments of the coronary arteries… Whereas IVUS focuses on the portion of the coronary tree with the least luminal narrowing, QCA focuses on the portion with the greatest luminal narrowing.” However, 1 of 2 primary efficacy parameters in the IVUS study was the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. Measured segments may have not been different in both IVUS and QCA studies.1,2 To clarify this point, it would be of great help if the authors would clarify how different segments were measured by angiography versus IVUS.DisclosuresNone. References 1 Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif JC, Brener SJ, Cain VA, Nissen SE. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden. Circulation. 2008; 117: 2458–2466.LinkGoogle Scholar2 Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006; 295: 1556–1565.CrossrefMedlineGoogle Scholar3 Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006; 145: 520–530.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Yan L, Zhu T, Wang L, Pan S, Tao Z, Yang Z, Cao K and Huang J (2010) Inhibitory effect of hepatocyte growth factor on cardiomyocytes apoptosis is partly related to reduced calcium sensing receptor expression during a model of simulated ischemia/reperfusion, Molecular Biology Reports, 10.1007/s11033-010-0412-8, 38:4, (2695-2701), Online publication date: 1-Apr-2011. November 25, 2008Vol 118, Issue 22 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.803189PMID: 19029473 Originally publishedNovember 25, 2008 PDF download Advertisement SubjectsImagingMechanismsMetabolismPathophysiology

Effect of Hepatocyte Growth Factor on Gene Expression of Extracellular Matrix during Wound Healing of the Injured Rat Vocal Fold

We performed a prospective, sham-controlled animal study to investigate the effects of hepatocyte growth factor (HGF) manipulation of the extracellular matrix on vocal fold gene expression during acute injury. Bilateral vocal fold wounds were created in 40 rats. The rats were randomly assigned to 1 of 2 groups (sham treatment or HGF treatment) and received treatment of the injured area at the time of wounding and on alternate posttreatment days. The injured vocal fold specimens were harvested on post-treatment days 1, 3, 7, and 14. We used real-time reverse transcription polymerase chain reaction to quantify messenger RNA expression of transforming growth factor (TGF)-beta1, procollagen types I and III, hyaluronan synthase (HAS)-1, HAS-2, and HAS-3. A multivariate analysis of variance revealed a significant interaction between treatment group and post-treatment day for TGF-beta1, procollagen type I, procollagen type III, and HAS-2. Post hoc testing revealed significantly lower expression of procollagen type III and significantly higher expression of HAS-2 on post-treatment day 14 in the HGF treatment group than in the sham treatment group. Results provide evidence of HGF treatment effects on procollagen type III and HAS-2 gene expression pathways.

Magnitude-dependent effects of cyclic stretch on HGF- and VEGF-induced pulmonary endothelial remodeling and barrier regulation

Mechanical ventilation at high tidal volumes compromises the blood-gas barrier and increases lung vascular permeability, which may lead to ventilator-induced lung injury and pulmonary edema. Using pulmonary endothelial cell (ECs) exposed to physiologically [5% cyclic stretch (CS)] and pathologically (18% CS) relevant magnitudes of CS, we evaluated the potential protective effects of hepatocyte growth factor (HGF) on EC barrier dysfunction induced by CS and vascular endothelial growth factor (VEGF). In static culture, HGF enhanced EC barrier function in a Rac-dependent manner and attenuated VEGF-induced EC permeability and paracellular gap formation. The protective effects of HGF were associated with the suppression of Rho-dependent signaling triggered by VEGF. Five percent CS promoted HGF-induced enhancement of the cortical F-actin rim and activation of Rac-dependent signaling, suggesting synergistic barrier-protective effects of physiological CS and HGF. In contrast, 18% CS further enhanced VEGF-induced EC permeability, activation of Rho signaling, and formation of actin stress fibers and paracellular gaps. These effects were attenuated by HGF pretreatment. EC preconditioning at 5% CS before HGF and VEGF further promoted EC barrier maintenance. Our data suggest synergistic effects of HGF and physiological CS in the Rac-mediated mechanisms of EC barrier protection. In turn, HGF reduced the barrier-disruptive effects of VEGF and pathological CS via downregulation of the Rho pathway. These results support the importance of HGF-VEGF balance in control of acute lung injury/acute respiratory distress syndrome severity via small GTPase-dependent regulation of lung endothelial permeability.

Effect of hepatocyte growth factor encapsulated in targeted liposomes on liver cirrhosis

Hepatocyte growth factor (HGF) was encapsulated into sterically stabilized liposomes (SSL) in order to protect it from in vivo degradation. Cyclic Arg-Gly-Asp (RGD) peptides were combined with maleimide-[poly (ethylene glycol)]-1,2-dioleoyl- sn-glycero-3-phosphoethanolamine (MAL-PEG-DOPE) incorporated into SSL. The average percentage of HGF encapsulated into liposomes was 32.38%, the size of liposomes was 91.56 nm and the polydispersity index was 0.164. In vivo, histological observation of the rat livers revealed that injection of RGD–SSL–HGF induced more significant remission of liver cirrhosis than injection of SSL–HGF, HGF alone, HGF plus RGD–SSL and saline. When the histological score, the collagen surface density, the hydroxyproline content and the expression of procollagen α1 (I) and α1 (III) mRNA in the liver were evaluated, all values were smallest in the RGD–SSL–HGF group. In contrast, an increase in apoptotic α-SMA-positive cells was noted in the RGD–SSL–HGF group. Together, this data suggests that targeted liposomes encapsulating HGF is a promising therapeutic modality in terms of promoting the remission of liver cirrhosis by promoting collagen fiber digestion, inhibiting collagen production, and promoting apoptosis of α-SMA-positive cells in rats with cirrhosis.

Hepatocyte growth factor improves survival after partial hepatectomy in cirrhotic rats suppressing apoptosis of hepatocytes

Liver failure after hepatic resection is still a critical issue in the treatment of hepatic tumors in patients with liver cirrhosis. In the current study, the effect of hepatocyte growth factor (HGF) gene transfer, which is a multipotent growth factor, was examined in rats with liver cirrhosis that underwent 2/3 partial hepatectomy (PH). Rats were treated with 1 mL of 1% dimethylnitrosoamine (DMN) 3 consecutive days per week for 4 weeks and then received a 2/3 PH. Three days before the PH, human HGF gene plasmid (20 microg) encapsulated in hemagglutinating virus of Japan (HVJ)-liposome was administered through a direct injection in the portal vein. Control cirrhotic rats received empty HVJ-liposome in the same manner. HGF gene transfer significantly improved survival after PH in the cirrhotic rats, and it stimulated BrdU uptake in hepatocytes. Although the HGF gene transfer did not change the liver regeneration rate after PH, it suppressed hepatocyte apoptosis and upregulated an antiapoptotic protein, Bcl-xl, but it did not affect the expression of Bax, which is a proapoptotic protein. HGF gene transfer to cirrhotic livers improves liver failure-associated death after PH upregulating expression of an antiapoptotic protein, Bcl-xl.