Reduced liver fibrosis in hypoxia-inducible factor-1 alpha-deficient mice
ABSTRACT Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1alpha (HIF-1alpha) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1alpha protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1alpha is required for the development of fibrosis, control and HIF-1alpha-deficient mice were subjected to BDL. Levels of type I collagen and alpha-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1alpha-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1alpha promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1alpha-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1alpha is a critical regulator of profibrotic mediator production during the development of liver fibrosis.
- SourceAvailable from: Satdarshan (Paul) Singh Monga[Show abstract] [Hide abstract]
ABSTRACT: Platelet-derived growth factor receptor α (PDGFRα) is an isoform of the PDGFR family of tyrosine kinase receptors involved in cell proliferation, survival, differentiation, and growth. In this review, we highlight the role of PDGFRα and the current evidence of its expression and activities in liver development, regeneration, and pathology—including fibrosis, cirrhosis, and liver cancer. Studies elucidating PDGFRα signaling in processes ranging from profibrotic signaling, angiogenesis, and oxidative stress to epithelial-to-mesenchymal transition point toward PDGFRα as a potential therapeutic target in various hepatic pathologies, including hepatic fibrosis and liver cancer. Furthermore, PDGFRα localization and modulation during liver development and regeneration may lend insight into its potential roles in various pathologic states. We will also briefly discuss some of the current targeted treatments for PDGFRα, including multireceptor tyrosine kinase inhibitors and PDGFRα-specific inhibitors.Gene Expression 02/2015; 16(3). DOI:10.3727/105221615X14181438356210 · 1.67 Impact Factor
Article: Angiogenesis and liver fibrosis[Show abstract] [Hide abstract]
ABSTRACT: Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.03/2015; 7(3):377-91. DOI:10.4254/wjh.v7.i3.377
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ABSTRACT: Liver fibrosis occurs as compensatory responses to tissue repairing process in a wide range of chronic liver injures. It is characterized by excessive deposition of extracellular matrix(ECM) in liver tissues. As the pathogenesis progresses without effective management, it will lead to formation of liver fiber nodules and disruption of normal liver structure and function, finally culminating in cirrhosis and hepatocellular carcinoma (HCC). The newly discoveryshows thatliver angiogenesis is strictly associated with, and mayeven favor fibrogenic progression of chronicliver diseases.Recent basic and clinical investigations also demonstrate that liver fibrogenesis is accompanied by pathological angiogenesis and sinusoidal remodeling, which critically determine the pathogenesis and prognosis of liver fibrosis.Inhibition of pathological angiogenesis is considered to be a new strategy for the treatment of liver fibrosis. This review summarizes current knowledge on the process of angiogenesis, the relationships between angiogenesis and liver fibrosis,and on the molecularmechanisms of liver angiogenesis. On the other hand, it also presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and the role of angiogenesis in the prevention and treatment of liver fibrosis.Hepatology Research 09/2014; 45(2). DOI:10.1111/hepr.12415 · 2.22 Impact Factor