Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.
BACKGROUND
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.


METHODS AND RESULTS
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.


CONCLUSIONS
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.
['Haller|Steven T|ST|', 'Yan|Yanling|Y|', 'Drummond|Christopher A|CA|', 'Xie|Joe|J|', 'Tian|Jiang|J|', 'Kennedy|David J|DJ|', 'Shilova|Victoria Y|VY|', 'Xie|Zijian|Z|', 'Liu|Jiang|J|', 'Cooper|Christopher J|CJ|', 'Malhotra|Deepak|D|', 'Shapiro|Joseph I|JI|', 'Fedorova|Olga V|OV|', 'Bagrov|Alexei Y|AY|']
D000818:Animals D001794:Blood Pressure D002018:Bufanolides D009202:Cardiomyopathies D002478:Cells, Cultured D004791:Enzyme Inhibitors D005347:Fibroblasts D005355:Fibrosis D006321:Heart D006801:Humans D007166:Immunosuppressive Agents D008297:Male D009206:Myocardium D009392:Nephrectomy D051381:Rats D017207:Rats, Sprague-Dawley D020123:Sirolimus D000254:Sodium-Potassium-Exchanging ATPase D014511:Uremia
cardiac fibrosis fibrosis cardiomyopathy cardiovascular diseases heart failure