Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.
Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.
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DOI：
10.1161/jaha.116.004106
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发表时间：
2016-09-30
影响因子：
5.4
通讯作者：
Bagrov AY
中科院分区：
文献类型：
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作者：
Haller ST;Yan Y;Drummond CA;Xie J;Tian J;Kennedy DJ;Shilova VY;Xie Z;Liu J;Cooper CJ;Malhotra D;Shapiro JI;Fedorova OV;Bagrov AY
实验性尿毒症心肌病导致心脏纤维化，并与强心类固醇Marinobufagenin（MBG）的循环水平增加有因果关系，MBG通过Na/K-ATP酶发出信号。雷帕霉素是丝氨酸/苏氨酸激酶哺乳动物雷帕霉素靶蛋白（mTOR）的抑制剂，与许多不同形式的肾脏疾病的进展有关。鉴于已知Na/K-ATP酶信号传导刺激mTOR系统，我们推测雷帕霉素的改善作用可能会影响这一途径。培养的人JEG-3细胞的MBG生物合成由CYP 27 A1启动，CYP 27 A1也是雷帕霉素的靶点。结果表明，1 μmol/L雷帕霉素抑制人JEG-2细胞中MBG的产生。对雄性Sprague-道利大鼠进行肾部分切除术（PNx）、输注MBG和/或通过渗透微型泵输注雷帕霉素。与对照组相比，PNx动物的血浆MBG水平（1025±60 vs 377±53 pmol/L; P<0.01）、收缩压（169±1 vs 111±1 mm Hg; P<0.01）和心脏纤维化显著增加。与PNx相比，PNx-雷帕霉素动物的血浆MBG水平显著降低（373±46 vs 1025±60 pmol/L; P<0.01），雷帕霉素治疗显著减轻了心脏纤维化。雷帕霉素治疗与MBG输注组合显著减弱心脏纤维化。我们的研究结果表明，雷帕霉素可能通过（1）mTOR抑制和（2）抑制MBG介导的促纤维化信号传导对心脏纤维化具有双重作用，并为尿毒症心肌病新疗法的有益作用提供支持。
Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K‐ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. Biosynthesis of MBG by cultured human JEG‐3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; P<0.01), systolic blood pressure (169±1 vs 111±1 mm Hg; P<0.01), and cardiac fibrosis compared to controls. Plasma MBG levels were significantly decreased in PNx‐rapamycin animals compared to PNx (373±46 vs 1025±60 pmol/L; P<0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment. Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG‐mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy.