Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca2+- and phosphoinositide 3-kinase/Akt-dependent phosphorylation in aortic endothelial cells

Makondo, Kennedy; Kimura, Kazuhiro; Naoki, Katsuhiko; Kitamura, Takanori; Yamaji, Daisuke; Jung, Bae Dong; Saito, Masayuki

doi:10.1042/bj20030326

Cited by 33 publications

(32 citation statements)

References 30 publications

(41 reference statements)

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“…Under physiological conditions, the activation of this growth factor results in an increase of the intracellular Ca 2+ concentration, which can be responsible for the direct activation of the eNOS [25]. As it has been demonstrated that HGF increases the endothelial NO generation [26], we examined whether this effect of HGF is affected by the inhibition of the BK Ca . We observed a significant reduction of the HGF-induced cGMP levels if the cells were treated with IBX.…”

Section: Discussionmentioning

confidence: 99%

A new signaling mechanism of hepatocyte growth factor‐induced endothelial proliferation

Kuhlmann¹,

Schaefer²,

Fehsecke

et al. 2005

Journal of Thrombosis and Haemostasis

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Summary. Background: The hepatocyte growth factor (HGF) has been shown to promote endothelial cell proliferation. In this study, the signaling cascade responsible for the HGF-induced proliferation was examined. Methods: The proliferation of human umbilical cord vein endothelial cells (HUCVEC) was determined using cell counts. Changes of the membrane potential were analyzed using the fluorescence dye DiBAC. Intracellular cGMP-levels were measured by means of [ ). A HGF-induced hyperpolarization that was blocked by iberiotoxin was observed. In addition, HGF-induced activation of the eNOS was blocked by the K + channel inhibitor. An increase of +101% MAPK phosphorylation was induced by HGF, which was blocked, if the cells were treated with L-NMMA (n ¼ 20; P < 0.05), whereas HGF-induced phosphorylation of the eNOS was not affected by MEK inhibition. Conclusions: Hepatocyte growth factor modulates endothelial K + channels causing an activation of the eNOS; the increase of nitric oxide is necessary for the phosphorylation of the MAPK inducing the proliferation of HUCVEC.

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Section: Discussionmentioning

confidence: 99%

A new signaling mechanism of hepatocyte growth factor‐induced endothelial proliferation

Kuhlmann¹,

Schaefer²,

Fehsecke

et al. 2005

Journal of Thrombosis and Haemostasis

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“…Upon activation by HGF, c-met PTK activity is coupled to the recruitment of several adaptor proteins including the non-receptor PTK Src, the adaptor protein SHC, growth factor receptor-bound protein 2 (Grb2), and Grb-2-associated binder (Gab1) (Peruzzi & Bottaro 2006), followed by mobilization of numerous signaling cascades. Examples of HGF-induced signaling motifs include those mediated by cyclic nucleotides, phosphosinositide-3 kinase (PI-3K)/protein kinase B (Akt), mitogen-activated protein kinases, calcium-phospholipids/protein kinase C, and Janus kinase/signal transducer and activator of transcription (Baffy et al 1992, Lail-Trecker et al 1998, Liu 1999, Zachow & Woolery 2002, Makondo et al 2004. Pathways coupled to the regulation of cell cycle progression, morphogenesis, and cell survival are among those under the control of HGF/c-met-dependent signaling (Peruzzi & Bottaro 2006).…”

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confidence: 99%

The hepatocyte growth factor system as a regulator of female and male gonadal function

Zachow

Uzumcu²

2007

Journal of Endocrinology

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The hepatocyte growth factor (HGF) system comprises HGF, its receptor (the c-met tyrosine kinase), HGF activator (HGFA) protein, and HGFA inhibitor (HAI). The components of the HGF system have been identified in a plethora of tissues to include the ovary and testis. In its traditional context, the HGF system works via paracrine-and autocrine-mediated feedback in which HGF (of mesenchymal origin) binds and activates c-met (within epithelial cells); target cells then respond to HGF via any number of morphogenic and functional changes. The concomitant presence of HGFA and HAI suggests that HGF bioactivity can be locally modulated. A number of studies have collectively shown that the mammalian ovary and testis contain HGF, c-met, and HGFA; very little is currently known regarding HAI within the gonad. Within the ovary, HGF controls numerous key functions which collectively regulate the growth and differentiation of ovarian follicles; these include cell growth, steroidogenesis, and apoptosis within theca cells and/or granulosa cells. Comparatively, less is known about the function of HGF within the testicular Leydig and Sertoli cells, but evidence is emerging that HGF may regulate somatic cell function, including Leydig cell steroidogenesis. Changes in the cellular origin of HGF and c-met during fetal and postnatal testicular development suggest that HGF, in collaboration with other growth factors, may regulate important aspects of testicular cell morphogenesis and differentiation which enable male sexual viability. Likewise, experimental evidence showing that HGF can modulate many vital processes which enable ovarian follicle growth, differentiation, and function indicate the importance of HGF in female reproduction. This review presents what is currently known regarding the expression of the HGF system and its function within the ovary and testis.

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“…These differences between telmisartan and losartan might be due to an increase in vascular HGF level. HGF is known to activate eNOS phosphorylation and increase NO production through the phosphoinositide 3-kinase/Akt pathway (11,12). Moreover, previous reports have documented that HGF induced re- …”

Section: Discussionmentioning

confidence: 99%

Differential response of vascular hepatocyte growth factor concentration and lipid accumulation between telmisartan and losartan in ApoE-deficient mice

Nakagami¹

2008

Mol Med Rep

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Abstract. The favorable metabolic effects of telmisartan have been related to its blockade of angiotensin (Ang) II receptor and action as a partial agonist of peroxisome proliferatoractivated receptor γ (PPARγ). We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. ApoE-deficient mice were fed a high-fat diet with or without telmisartan (10 mg/kg/day) or losartan (30 mg/kg/day) for 3 months. Treatment with telmisartan or losartan significantly reduced blood pressure, but did not affect serum cholesterol, triglyceride or glucose levels. Both drugs inhibited the development of lipid-rich plaque as assessed by oil red O staining. However, treatment with telmisartan, but not losartan, significantly improved endothelial dysfunction as assessed by the vasodilator response to acetylcholine. To elucidate the molecular mechanisms of the differential response in the improvement of endothelial dysfunction between telmisartan and losartan, we next focused on the expression of various cytokines. As both telmisartan and losartan attenuated interleukin-6 mRNA expression in the aorta, there was a significant change in endothelial nitric oxide synthase (eNOS) mRNA in the aorta. Notably, telmisartan, but not losartan, significantly increased the expression of hepatocyte growth factor (HGF), but not that of vascular endothelial growth factor (VEGF) in the aorta. Although a decrease in body weight and adipose tissue weight was observed with both telmisartan and losartan, liver weight was significantly decreased in only the telmisartan-treated group. Of importance, telmisartan markedly inhibited lipid accumulation in the liver. Overall, telmisartan and losartan induced differential responses in the improvement of endothelial dysfunction, probably due to their effects on vascular HGF levels and fatty liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPARγ, beyond its blood pressure-lowering effect, through Ang II blockade. IntroductionHigh blood pressure is closely associated with insulin resistance and dyslipidemia. Thus, current antihypertensive drugs should be designed to affect the cellular and biochemical mechanisms that contribute to an increase in blood pressure, and should also address the disordered lipid metabolism that often accompanies hypertension as part of the metabolic syndrome. Telmisartan, an angiotensin (Ang) type I receptor (AT1R) blocker (ARB), has been widely used in the treatment of hypertension and hypertension-related cardiovascular endorgan damage (1). When tested at concentrations that may be present in plasma with oral doses used for the treatment of hypertension, it was also identified as a unique moderately potent selective partial agonist of peroxisome proliferatoractivated receptor γ (PPARγ) (2,3).PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity, reduce triglyceride (TG) levels and decrease the risk of atherosclerosis (4-6). A recent cl...

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Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca2+- and phosphoinositide 3-kinase/Akt-dependent phosphorylation in aortic endothelial cells

Cited by 33 publications

References 30 publications

A new signaling mechanism of hepatocyte growth factor‐induced endothelial proliferation

A new signaling mechanism of hepatocyte growth factor‐induced endothelial proliferation

The hepatocyte growth factor system as a regulator of female and male gonadal function

Differential response of vascular hepatocyte growth factor concentration and lipid accumulation between telmisartan and losartan in ApoE-deficient mice

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