Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C
Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C
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DOI：
10.1152/ajpgi.00162.2009
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发表时间：
2009-10-01
影响因子：
4.5
通讯作者：
Gines, Pere
中科院分区：
文献类型：
--
作者：
Colmenero, Jordi;Bataller, Ramon;Gines, Pere
科尔梅内罗J，巴塔勒R，桑乔 - 布鲁P，多明格斯M，莫雷诺M，福恩斯X，布鲁格拉M，阿罗约V，布伦纳DA，希内斯P。氯沙坦对慢性丙型肝炎患者肝脏非吞噬性NADPH氧化酶及纤维化基因表达的影响。《美国生理学杂志 - 胃肠肝生理学》297卷：G726 - G734，2009年。首次发表于2009年7月23日；doi:10.1152/ajpgi.00162.2009。 - 血管紧张素II通过刺激非吞噬性NADPH氧化酶（NOX）诱导的氧化应激促进肝纤维化。血管紧张素II 1型（AT1）受体阻滞剂可减轻实验性肝纤维化，但其在人类肝纤维化中的作用尚不清楚。我们研究了氯沙坦对慢性丙型肝炎（CHC）患者肝脏纤维化、炎症及NOX基因表达的影响。14名患有CHC和肝纤维化的患者口服氯沙坦（50mg/天）18个月。在基线和治疗后进行肝活检。通过组织学分析（METAVIR）评估炎症和纤维化程度。通过天狼星红染色的形态计量定量测量胶原含量。在整个系列中，总体胶原含量和纤维化分期保持稳定，但7名患者的纤维化分期降低。7名患者的炎症活动改善。通过定量PCR评估氯沙坦对31种促纤维化和炎症基因以及NOX复合物成分的肝脏表达的影响。氯沙坦治疗与几种促纤维化和NOX基因的表达显著降低有关，这些基因包括I型前胶原α1和IV型前胶原α1、尿激酶型纤溶酶原激活物、2型金属蛋白酶、NOX激活剂1（NOXA - 1）和组织者1（NOXO - 1）以及Rac - 1。所有患者对氯沙坦耐受性良好，且能有效减弱全身肾素 - 血管紧张素系统的活性。未观察到对血清肝功能检查或病毒载量的影响。我们得出结论，长期口服AT1受体阻滞剂氯沙坦与CHC患者NOX成分和纤维化基因的下调有关。有必要进行对照研究以评估AT1受体阻滞剂在慢性肝损伤中的作用。
Colmenero J, Bataller R, Sancho-Bru P, Dominguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Gines P. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297: G726-G734, 2009. First published July 23, 2009; doi: 10.1152/ajpgi.00162.2009.-Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen alpha 1(I) and alpha 1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.