Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / metabolism
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / therapeutic use*
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Blood Pressure / drug effects
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Body Weight / drug effects
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Cholesterol, Dietary
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Cytokines / blood
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Diet, High-Fat
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Disease Progression*
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Extracellular Matrix / metabolism*
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Gene Expression Regulation / drug effects
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Hydralazine / administration & dosage
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Hydralazine / pharmacology
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Hydralazine / therapeutic use*
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Hypertension / complications*
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Hypertension / drug therapy*
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Hypertension / physiopathology
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Liver Cirrhosis / blood
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Liver Cirrhosis / complications
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Liver Cirrhosis / drug therapy*
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Liver Cirrhosis / pathology
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Matrix Metalloproteinases / blood
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Models, Biological
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Non-alcoholic Fatty Liver Disease / blood
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Non-alcoholic Fatty Liver Disease / complications
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Non-alcoholic Fatty Liver Disease / drug therapy*
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Non-alcoholic Fatty Liver Disease / pathology
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Organ Size / drug effects
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Rats, Inbred SHR
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Rats, Inbred WKY
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Tissue Inhibitor of Metalloproteinase-1 / blood
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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Antihypertensive Agents
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CD68 antigen, human
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Cholesterol, Dietary
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Cytokines
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Tissue Inhibitor of Metalloproteinase-1
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Hydralazine
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Matrix Metalloproteinases
Grants and funding
The work has been supported by Grants-in-Aid for Scientific Research (B15H04788, C16K00877, C18K10033, and C19K10583).