Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice

Fatemeh Momen-Heravi; Donna Catalano; Austin Talis; Gyongyi Szabo; Shashi Bala

doi:10.1016/j.omtn.2021.05.007

Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice

Fatemeh Momen-Heravi, Donna Catalano, Austin Talis, Gyongyi Szabo, Shashi Bala

College of Dental Medicine

Producción científica › revisión exhaustiva

17 Citas (Scopus)

Resumen

microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl₄ and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl₄-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl₄ treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.

Idioma original	English
Páginas (desde-hasta)	155-167
Número de páginas	13
Publicación	Molecular Therapy Nucleic Acids
Volumen	25
DOI	https://doi.org/10.1016/j.omtn.2021.05.007
Estado	Published - sep. 3 2021

Financiación

The authors thank Dr. Victor Ambros for his valuable suggestions and Dr. Timea Csak for her assistance in animal experiments. This work was supported by startup funds to S.B. by the Department of Medicine, University of Massachusetts Medical School ; by grant AA020744 to G.S.; and by grants from the Columbia University Irving Medical Center , the Columbia University College of Dental Medicine , the Irving Institute for Clinical and Translational Research ( UL1 TR001873 ), and Herbert Irving Comprehensive Cancer Center Multi PI grant ( P30 CA013696 ) to F.M.H. G.S. reports being a paid consultant for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. G.S. has received grants from Gilead, Genfit, Intercept, Novartis, SignaBlok, and Shire; she also holds intellectual property rights with UpToDate. All other authors declare no competing interests. The authors thank Dr. Victor Ambros for his valuable suggestions and Dr. Timea Csak for her assistance in animal experiments. This work was supported by startup funds to S.B. by the Department of Medicine, University of Massachusetts Medical School; by grant AA020744 to G.S.; and by grants from the Columbia University Irving Medical Center, the Columbia University College of Dental Medicine, the Irving Institute for Clinical and Translational Research (UL1 TR001873), and Herbert Irving Comprehensive Cancer Center Multi PI grant (P30 CA013696) to F.M.H. F.M.H.: conceptualization, methodology, validation, investigation, formal analysis, writing, visualization, and funding acquisition. D.C.: investigation. A.T.: writing, review, and editing. G.S.: resources. S.B.: conceptualization, methodology, validation, investigation, formal analysis, visualization, writing, supervision, and funding acquisition. G.S. reports being a paid consultant for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. G.S. has received grants from Gilead, Genfit, Intercept, Novartis, SignaBlok, and Shire; she also holds intellectual property rights with UpToDate. All other authors declare no competing interests.

Financiadores	Número del financiador
Alnylam
Department of Medicine, University of Massachusetts Medical School	AA020744
Gilead Sciences
Institute for Clinical and Translational Research, University of Wisconsin, Madison	UL1 TR001873, P30 CA013696
Allergan
College of Dental Medicine, Columbia University
Irving Medical Center, Columbia University
Shire

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

ODS de las Naciones Unidas

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abstract = "microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.",

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N2 - microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.

AB - microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.

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Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice

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