Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro‐Fibrotic Signaling Article (Web of Science)

abstract

  • 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‐ ATP ase. 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‐ ATP ase 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 CYP 27A1, 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 ( PN x), infusion of MBG , and/or infusion of rapamycin through osmotic minipumps. PN x 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 PN x‐rapamycin animals compared to PN x (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.

authors

publication date

  • 2016

webpage

published in

volume

  • 5

issue

  • 10