Low Cardiac Output Leads Hepatic Fibrosis in Right Heart Failure Model Rats.
Low Cardiac Output Leads Hepatic Fibrosis in Right Heart Failure Model Rats.
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DOI：
10.1371/journal.pone.0148666
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Minamisawa S
中科院分区：
文献类型：
--
作者：
Fujimoto Y;Urashima T;Shimura D;Ito R;Kawachi S;Kajimura I;Akaike T;Kusakari Y;Fujiwara M;Ogawa K;Goda N;Ida H;Minamisawa S
肝纤维化进展伴右心衰竭，严重者发展为心源性肝硬化。尽管其因果关系仍不清楚。在这里，我们使用肺动脉结扎（PAB）诱导的右心衰竭模型评估肝纤维化的进展，并研究心输出量（CO）是否是肝纤维化进展的原因。5周龄Sprague-Dawley大鼠分为PAB组和假手术对照组。术后4周，超声心动图检测CO，彩色分析仪检测肝纤维化率。PAB组CO较对照组降低48%（78.2±27.6和150.1± 31.2ml/min，P<0.01）。PAB组肝纤维化率和肝纤维化指标血清透明质酸均显著高于对照组（7.8±1.7和1.0± 0.2%，P<0.01; 76.2±27.5和32.7± 7.5ng/ml，P<0.01）。值得注意的是，肝纤维化的程度显着相关的CO的减少。免疫组织化学分析显示，肝星状细胞显着激活缺氧区，HIF-1α阳性肝细胞增加PAB组。此外，通过实时PCR分析，PAB组中促纤维化和纤维化因子（TGF-β1、CTGF、前胶原I、前胶原III、MMP 2、MMP 9、TIMP 1、TIMP 2）的转录显著增加。Western blot结果显示，PAB组HIF-1α蛋白水平明显高于对照组（2.31±0.84和1.0±0.18任意单位，P<0.05）。我们的研究表明，低CO和组织缺氧是右心衰竭模型大鼠肝纤维化的原因。
Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis using a pulmonary artery banding (PAB)-induced right heart failure model and investigated whether cardiac output (CO) is responsible for the progression of hepatic fibrosis. Five-week-old Sprague-Dawley rats divided into the PAB and sham-operated control groups. After 4 weeks from operation, we measured CO by echocardiography, and hepatic fibrosis ratio by pathological examination using a color analyzer. In the PAB group, CO was significantly lower by 48% than that in the control group (78.2±27.6 and 150.1±31.2 ml/min, P<0.01). Hepatic fibrosis ratio and serum hyaluronic acid, an index of hepatic fibrosis, were significantly increased in the PAB group than those in the control group (7.8±1.7 and 1.0±0.2%, P<0.01, 76.2±27.5 and 32.7±7.5 ng/ml, P<0.01). Notably, the degree of hepatic fibrosis significantly correlated a decrease in CO. Immunohistological analysis revealed that hepatic stellate cells were markedly activated in hypoxic areas, and HIF-1α positive hepatic cells were increased in the PAB group. Furthermore, by real-time PCR analyses, transcripts of profibrotic and fibrotic factors (TGF-β1, CTGF, procollargen I, procollargen III, MMP 2, MMP 9, TIMP 1, TIMP 2) were significantly increased in the PAB group. In addition, western blot analyses revealed that the protein level of HIF-1α was significantly increased in the PAB group than that in the control group (2.31±0.84 and 1.0±0.18 arbitrary units, P<0.05). Our study demonstrated that low CO and tissue hypoxia were responsible for hepatic fibrosis in right failure heart model rats.