Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.
University of Barcelona Medical School, Barcelona, Spain.
Hepatology. 2017 Jun;65(6):2031-2044. doi: 10.1002/hep.29084. Epub 2017 May 2.
In cirrhosis, increased intrahepatic vascular resistance (IHVR) is the primary factor for portal hypertension (PH) development. Hepatic stellate cells (HSCs) play a major role increasing IHVR because, when activated, they are contractile and promote fibrogenesis. Protease-activated receptors (PARs) can activate HSCs through thrombin and factor Xa, which are known PAR agonists, and cause microthrombosis in liver microcirculation. This study investigates the effects of the oral anticoagulant, rivaroxaban (RVXB), a direct antifactor Xa, on HSC phenotype, liver fibrosis (LF), liver microthrombosis, and PH in cirrhotic rats. Hepatic and systemic hemodynamic, nitric oxide (NO) bioavailability, LF, HSC activation, and microthrombosis were evaluated in CCl and thioacetamide-cirrhotic rats treated with RVXB (20 mg/kg/day) or its vehicle for 2 weeks. RVXB significantly decreased portal pressure (PP) in both models of cirrhosis without changes in portal blood flow, suggesting a reduction in IHVR. RVXB reduced oxidative stress, improved NO bioavailability, and ameliorated endothelial dysfunction. Rivaroxaban deactivated HSC, with decreased alpha-smooth muscle actin and mRNA expression of other HSC activation markers. Despite this marked improvement in HSC phenotype, no significant changes in LF were identified. RVXB markedly reduced fibrin deposition, suggesting reduced intrahepatic microthrombosis.
RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031-2044).
在肝硬化中，肝内血管阻力（IHVR）增加是门静脉高压（PH）发展的主要因素。肝星状细胞（HSCs）在增加 IHVR 方面起着主要作用，因为当它们被激活时，它们是收缩性的，并促进纤维化。蛋白酶激活受体（PARs）可以通过已知的 PAR 激动剂凝血酶和因子 Xa 激活 HSCs，并在肝微循环中引起微血栓形成。本研究探讨了口服抗凝剂利伐沙班（RVXB），一种直接的因子 Xa 抑制剂，对肝硬化大鼠 HSC 表型、肝纤维化（LF）、肝微血栓形成和 PH 的影响。在 CCl 和硫代乙酰胺诱导的肝硬化大鼠中，评估了 RVXB（20mg/kg/天）或其载体治疗 2 周后的肝和全身血液动力学、一氧化氮（NO）生物利用度、LF、HSC 激活和微血栓形成。RVXB 显著降低了两种肝硬化模型的门脉压（PP），而门脉血流量无变化，提示 IHVR 降低。RVXB 降低了氧化应激，改善了 NO 生物利用度，并改善了内皮功能障碍。利伐沙班使 HSC 失活，α-平滑肌肌动蛋白减少，其他 HSC 激活标志物的 mRNA 表达减少。尽管 HSC 表型有明显改善，但 LF 无明显变化。RVXB 显著减少纤维蛋白沉积，提示肝内微血栓形成减少。
RVXB 降低了两种大鼠肝硬化模型的 PP。这种作用主要与 IHVR 降低、NO 生物利用度增加、HSC 失活和肝内微血栓形成减少有关。我们的研究结果表明，RVXB 作为治疗肝硬化 PH 的潜在药物值得进一步研究。（Hepatology 2017;65:2031-2044）。
