KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins
Abstract
Objective In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis. Design Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats. Results KLF2 upregulation profoundly ameliorated HSC phenotype (reduced α-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats tr…
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In models of liver fibrosis, DLL4 promotes capillarization and liver scarring, whereas KLF2 maintains endothelial integrity.
“Interestingly, in models of liver fibrosis, DLL4 promotes capillarization and liver scarring, whereas KLF2 maintains endothelial integrity”
From Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages (2020) · cites this paper as Marrone et al., 2015
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- Authors
- Marrone, G., Maeso-Díaz, R., García-Cardena, G., Abraldes, J. G., García-Pagán, J. C., Bosch, J., & Gracia-Sancho, J.
- Affiliations
- Hospital Clínic de Barcelona (ES)
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
- Departments of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, USA
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-12-10
- Volume
- 64
- Issue
- 9
- Pages
- 1434-1443
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W1997485766
- Cited by
- 222
- References
- 1
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 22 · 2023: 27 · 2022: 20 · 2021: 17 · 2020: 20 · 2019: 14 · 2018: 22 · 2017: 21 · 2016: 15 · 2015: 13 · 2014: 1
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- European Regional Development Fund
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- KLF2, liver cirrhosis, liver fibrosis, hepatic stellate cells, Nrf2, simvastatin, statins, portal hypertension, endothelial dysfunction, hepatic hemodynamics, vascular endothelial growth factor, paracrine signaling, hepatic sinusoidal endothelial cells, oxidative stress, antifibrotic therapy
- MeSH terms
- Animals, Antifibrinolytic Agents, Cells, Cultured, Disease Models, Animal, Gene Expression Regulation, Humans, Liver Cirrhosis, Male, Phenotype, Random Allocation, Sensitivity and Specificity, Up-Regulation, Rats, Wistar, Simvastatin, Protective Agents, Rats, Kruppel-Like Transcription Factors, Hepatic Stellate Cells, Molecular Targeted Therapy
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