Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats

Mejías, Marc; Coch, Laura; Berzigotti, Annalisa; García-Pras, Ester; Gallego, Javier González; Bosch, Jaime; Fernández, Mercedes

doi:10.1136/gutjnl-2014-307138

Cited by 52 publications

(34 citation statements)

References 40 publications

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“…Nevertheless, the antiangiogenic actions of AdPEDF were only modest when the adenovirus was given during the advanced stage. 93 …”

Section: Pigment Epithelium-derived Factormentioning

confidence: 97%

Molecular mechanisms of circulatory dysfunction in cirrhotic portal hypertension

Huang

2015

Journal of the Chinese Medical Association

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Acute or chronic insults to the liver are usually followed by a tissue repairing process. Unfortunately, this action, in most cases, is not effective enough to restore the normal hepatic structure and function. Instead, fibrogenesis and regenerative nodules formation ensue, which are relatively nonfunctioning. The common final stage of the process is liver cirrhosis with increased intrahepatic resistance to portal venous blood flow. Throughout the entire course, the extrahepatic circulatory dysfunction, including increased splanchnic blood flow, elevated portal venous blood flow and pressure, decreased splanchnic and peripheral vascular resistance, tachycardia, and increased cardiac output, are noted and denoted as portal hypertension with hyperdynamic circulatory dysfunction. When such a condition is established, patients may suffer from fatal complications such as gastroesophageal variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome. The cause of such a circulatory dysfunction is not fully elucidated. Nevertheless, clarification of the pathophysiology definitely contributes to the control of portal hypertension-related complications. Herein, the molecular mechanism of this intriguing disaster is reviewed and discussed.

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“…Nevertheless, the antiangiogenic actions of AdPEDF were only modest when the adenovirus was given during the advanced stage. 93 …”

Section: Pigment Epithelium-derived Factormentioning

confidence: 97%

Molecular mechanisms of circulatory dysfunction in cirrhotic portal hypertension

Huang

2015

Journal of the Chinese Medical Association

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“…Angiogenesis inhibition targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and/or pigment epithelium-derived growth factor (PEDF) pathways showed marked positive effects on portal hypertension [70,71]. Nevertheless, very recent data introduced two interesting novel concepts regarding targeting angiogenesis in cirrhosis: (1) VEGF has a dual role in cirrhosis, namely, it promotes fibrogenesis during disease progression, but it is completely necessary for fibrosis resolution [72], and (2) inhibition of pathological angiogenesis through the up-regulation of the endogenous angioinhibitor vasohibin-1 reveals remarkable beneficial effects, totally comparable to exogenously administered anti-angiogenesis drugs [73].…”

Section: Arachidonic Acid-derived Vasoconstriction Can Bementioning

confidence: 99%

New cellular and molecular targets for the treatment of portal hypertension

et al. 2015

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Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.

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“…PEDF has been suggested to be a potential therapeutic agent in NASH and liver fibrosis putatively by directly inhibiting hepatic stellate cell activation or by upregulating matrix metalloproteinase 2 (19,20). In addition, knockout of PEDF or gene transfer to the liver also demonstrated its role in steatosis (21,42), although the precise molecular events underlying those results remain obscure.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium‐derived factor expression

et al. 2018

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Hepatocellular death or ballooning distinguishes the transition of simple steatosis to irreversible nonalcoholic steatohepatitis (NASH). However, the molecular mechanism of hepatocellular apoptosis in NASH is largely unclear, and discovery of endogenous mediators that could prevent or inhibit cell death is thereby critical in intercepting NASH progression. Here, we identified pigment epithelium-derived factor (PEDF), a secreted, moonlighting hepatokine as 1 hepatoprotective agent in mice with diet-induced NASH. Hepatic PEDF expression is induced by IL-1β, which is derived from inflammasome activation in liver-resident Kupffer cells, an effect that is negatively regulated by TNF-α and predominantly secreted by monocyte-derived, recruited, hepatic macrophages. Mechanistically, reciprocal and opposing roles for IL-1β and TNF-α in PEDF expression are mediated by differential activation of NF-κB. Although augmented TNF-α production leads to temporal reduction of PEDF expression in NASH, PEDF conversely abrogates TNF-α-mediated hepatocyte death by modulating the extrinsic apoptosis pathway. Thus, our study highlights PEDF as a functionally important hepatokine in NASH progression by linking inflammasome activation and hepatocellular death.-Adak, M., Das, D., Niyogi, S., Nagalakshmi, C., Ray, D., Chakrabarti, P. Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium-derived factor expression.

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Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats

Abstract: This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis.

Cited by 52 publications

References 40 publications

Molecular mechanisms of circulatory dysfunction in cirrhotic portal hypertension

Molecular mechanisms of circulatory dysfunction in cirrhotic portal hypertension

New cellular and molecular targets for the treatment of portal hypertension

Inflammasome activation in Kupffer cells confers a protective response in nonalcoholic steatohepatitis through pigment epithelium‐derived factor expression

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