PPAR伪 activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats

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• 作者：Aina Rodrí ; guez-Vilarrupla¹ ; ^{arodr@clinic.ub.es} ; Bà ; rbara Laviñ ; a¹ ; Hé ; ctor Garcí ; a-Calderó ; ¹ ; Lucia Russo¹ ; Eugenio Rosado¹ ; Nú ; ria Roglans² ; Jaume Bosch¹ ; Joan Carles Garcí ; a-Pagá ; n¹
• 关键词：PPAR伪 ; peroxisome proliferator-activated receptor 伪 ; CCl4 ; carbon tetrachloride ; MAP ; mean arterial pressure ; PP ; portal pressure ; PBF ; portal blood flow ; Mtx ; methoxamine ; 伪-SMA ; alfa smooth muscle actin ; NO ; nitric oxide ; TAA ; thioacetamide ; TG ; trig
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：May, 2012
• 卷：56
• 期：5
• 页码：1033-1039
• 文件大小：941 K

摘要

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Background & Aims

Peroxisome proliferator-activated receptor 伪 (PPAR伪) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPAR伪 activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl₄-cirrhotic rats.

Methods

Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25 mg/kg/day, n = 10) or its vehicle (n = 12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (伪-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB₂ production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers.

Results

CCl₄ cirrhotic rats treated with fenofibrate had a significantly lower PP (鈭?9%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB₂ production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed.

Conclusions

PPAR伪 activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis.