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

• Published in: PloS one 2020-12, Vol.15 (12), p.e0243846
• Main Authors: Yuan, Yuan, Naito, Hisao, Kitamori, Kazuya, Hashimoto, Sayuki, Asano, Tomomi, Nakajima, Tamie
• Format: Article
• Language: English
• Subjects: Actin; Agglomeration; Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Antihypertensives; Biology and Life Sciences; Blood pressure; Blood Pressure - drug effects; Body Weight - drug effects; Cholesterol; Cholesterol, Dietary; Collagen; Cytokines - blood; Dehydrogenases; Diet; Diet, High-Fat; Disease Progression; Drinking water; Drug therapy; Environmental effects; Experiments; Extracellular matrix; Extracellular Matrix - metabolism; Fatty liver; Fibrosis; Gelatinase A; Gelatinase B; Gene Expression Regulation - drug effects; Growth factors; Health sciences; High cholesterol diet; High fat diet; Hydralazine; Hydralazine - administration & dosage; Hydralazine - pharmacology; Hydralazine - therapeutic use; Hydrofluorocarbons; Hypertension; Hypertension - complications; Hypertension - drug therapy; Hypertension - physiopathology; Inflammation; Inflammatory response; Kinases; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver cirrhosis; Liver Cirrhosis - blood; Liver Cirrhosis - complications; Liver Cirrhosis - drug therapy; Liver Cirrhosis - pathology; Liver diseases; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Matrix metalloproteinase; Matrix metalloproteinases; Matrix Metalloproteinases - blood; Medical research; Medicine and Health Sciences; Metalloproteinase; Models, Biological; Muscles; Neutrophil collagenase; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - pathology; Organ Size - drug effects; Physiological aspects; Platelet-derived growth factor; Proteins; Rats, Inbred SHR; Rats, Inbred WKY; Risk analysis; Risk factors; Smooth muscle; Stroke; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - blood; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0243846

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.