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

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.

Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

“… 38 Meanwhile, Ang II can aggravate IR though activating insulin signaling pathways. 39 Yuan et al 40 found that mice with hypertension showed more severe LF than those without hypertension, and that cytokine activation and inflammation played an important role. RAS activation, IR, and inflammation are important pathophysiological mechanisms underlying the co-morbidity of hypertension and NAFLD.…”

Hypertension and Histopathology Severity of Non-Alcoholic Fatty Liver Disease Among Adults with Obesity: A Cross-Sectional Study

“…Animal studies have shown how hypertension promotes the inflammatory response and fibrosis of the liver by inducing increased aggregation of CD68-positive Kupffer cells and cytokines release, and by reduction of liver antioxidant capacity. 23,24 This could explain why hypertension also worsens liver fibrosis status, leading to the progression of NAFLD. Moreover, a trial evidenced that an antihypertensive drug was associated with improvement of liver fibrosis 25 , which could be a clue to the association between hypertension and NAFLD severity that should be studied further.…”