HGF regulates the activation of TGF‐β1 in rat hepatocytes and hepatic stellate cells

Narmada, Balakrishnan Chakrapani; Chia, Ser-Mien; Tucker-Kellogg, Lisa; Yu, Hanry

doi:10.1002/jcp.24143

Cited by 38 publications

(38 citation statements)

References 48 publications

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“…We observed, however, that mice receiving LSKL peptide had decreased activation of TGF-β1 consistent with previous reports. 17,19,[30][31][32] Our findings are similar to previous observations in a rat model of diabetes mellitus, where LSKL administration did not alter TSP-1 levels in myocardial extracts. 17 Expression of TGFBRI, TGFBRII, and Smad4 mRNA were significantly lower in mice receiving LSKL.…”

Section: Discussionsupporting

confidence: 90%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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Section: Discussionsupporting

confidence: 90%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

View full text Add to dashboard Cite

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“…TGF-β can also increase serum bilirubin concentration and may be responsible for an abnormal ICG retention rate. PAI-1 and TGF-β interfere with liver regeneration by suppressing hepatocyte growth factor (38). Although VEGF-A usually acts as a vasodilator, it can act as a vasoconstrictor under conditions of endothelial failure and hepatic sinusoidal injury (39).…”

Section: Discussionmentioning

confidence: 99%

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Hirata

Tajima

Miyashita

et al. 2017

Molecular Medicine Reports

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Abstract. Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total-bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

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“…Transforming growth factor (TGF)-β, activated by thrombospondin (20), causes collagen deposition in the perisinusoidal space and inhibits substance exchange in the space of Disse, resulting in bilirubin elevation and an abnormal ICG retention rate. PAI-1 and TGF-β interfere with liver regeneration by suppressing hepatocyte growth factor (21). VEGF-A, which usually acts as a vasodilator, may paradoxically act as a vasoconstrictor under conditions of endothelial failure (22).…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

Tajima

Ohta

Miyashita

et al. 2015

Molecular and Clinical Oncology

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Abstract.Oxaliplatin-based chemotherapy plays a central role in the treatment of patients with colorectal liver metastasis (CRLM). This treatment, however, has been associated with hepatic sinusoidal obstruction syndrome (SOS), a clinically important adverse effect characterized by a bluish hue of the liver, splenomegaly and thrombocytopenia, resulting in liver dysfunction. The significant association between the sinusoidal endothelium and platelets has suggested that oxaliplatin-based chemotherapy affects platelets in the liver. This study compared platelet counts in patients who did and did not receive oxaliplatin-based neoadjuvant chemotherapy (NAC). The peripheral blood platelet count was significantly lower in the NAC group (n=17) compared to that in the non-NAC, or control group (n=15) (P<0.05). The spleen index was also higher in the NAC group, although the difference was not significant. However, the spleens of the patients in the NAC group were significantly enlarged following treatment (P<0.01). Immunostaining for the platelet surface marker CD42b (glycoprotein Ib), revealed more platelets in the liver in the NAC compared to the control group, particularly in the centrilobular zone III, adjacent to the hepatic central vein and in contact with hepatocytes (P<0.01). The platelets present in the spaces of Disse, referred to as extravasated platelet aggregation (EPA), secrete a number of growth factors, including transforming growth factor-β, vascular endothelial growth factor-A, plasminogen activator inhibitor-1 and thromboxane A2. In conclusion, EPA may play an important role in the development of hepatic SOS. Moreover, antiplatelet drugs may prevent the onset of SOS and hepatic injury in patients treated with oxaliplatin-based chemotherapy for CRLM.

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HGF regulates the activation of TGF‐β1 in rat hepatocytes and hepatic stellate cells

Cited by 38 publications

References 48 publications

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

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