Cargando…

The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension

Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comp...

Descripción completa

Detalles Bibliográficos
Autores principales: Yuan, Yuan, Naito, Hisao, Kitamori, Kazuya, Hashimoto, Sayuki, Asano, Tomomi, Nakajima, Tamie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735612/
https://www.ncbi.nlm.nih.gov/pubmed/33315911
http://dx.doi.org/10.1371/journal.pone.0243846
_version_ 1783622668151422976
author Yuan, Yuan
Naito, Hisao
Kitamori, Kazuya
Hashimoto, Sayuki
Asano, Tomomi
Nakajima, Tamie
author_facet Yuan, Yuan
Naito, Hisao
Kitamori, Kazuya
Hashimoto, Sayuki
Asano, Tomomi
Nakajima, Tamie
author_sort Yuan, Yuan
collection PubMed
description Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
format Online
Article
Text
id pubmed-7735612
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-77356122020-12-22 The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension Yuan, Yuan Naito, Hisao Kitamori, Kazuya Hashimoto, Sayuki Asano, Tomomi Nakajima, Tamie PLoS One Research Article Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension. Public Library of Science 2020-12-14 /pmc/articles/PMC7735612/ /pubmed/33315911 http://dx.doi.org/10.1371/journal.pone.0243846 Text en © 2020 Yuan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Yuan, Yuan
Naito, Hisao
Kitamori, Kazuya
Hashimoto, Sayuki
Asano, Tomomi
Nakajima, Tamie
The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title_full The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title_fullStr The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title_full_unstemmed The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title_short The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
title_sort antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735612/
https://www.ncbi.nlm.nih.gov/pubmed/33315911
http://dx.doi.org/10.1371/journal.pone.0243846
work_keys_str_mv AT yuanyuan theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT naitohisao theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT kitamorikazuya theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT hashimotosayuki theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT asanotomomi theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT nakajimatamie theantihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT yuanyuan antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT naitohisao antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT kitamorikazuya antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT hashimotosayuki antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT asanotomomi antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension
AT nakajimatamie antihypertensiveagenthydralazinereducedextracellularmatrixsynthesisandliverfibrosisinnonalcoholicsteatohepatitisexacerbatedbyhypertension