Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy
Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy
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DOI：
10.1161/01.hyp.0000202594.82271.92
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发表时间：
2006-03-01
期刊：
影响因子：
8.3
通讯作者：
Shapiro, JI
中科院分区：
文献类型：
--
作者：
Kennedy, DJ;Vetteth, S;Shapiro, JI
慢性肾衰竭患者发展为以舒张功能障碍、心脏肥厚和全身氧化应激为特征的“尿毒症”心肌病。慢性肾衰竭患者也有心脏强直类固醇马里诺bufagenin （MBG）循环浓度增高。在此背景下，我们假设循环MBG升高可能与心肌病有关。首先，我们观察到，连续4周给予MBG（每天10 μ g/kg）引起的血浆MBG增加与第4周部分肾切除术相当。MBG输注引起意识血压、心脏重量和左心室松弛时间常数的增加，与部分肾切除术相似。MBG输注和部分肾切除术均观察到心肌肌浆网atp酶、心脏纤维化和全身氧化应激的表达降低。接下来，对大鼠进行MBG-BSA结合物或BSA对照的主动免疫，随后进行部分肾切除术。抗MBG免疫可减轻部分肾切除术后出现的心脏肥厚、舒张功能损害、心脏纤维化和全身氧化应激，但对意识血压无显著影响。这些数据表明，MBG浓度的增加在心脏病和肾功能衰竭的氧化应激状态中是重要的。
Patients with chronic renal failure develop a "uremic" cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG ( 10 mu g/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.