Skip to main content
Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling
Pharmaceutical Science and Research
  • Steven T. Haller, PhD
  • Yanling Yan, PhD, Marshall University
  • Christopher A. Drummond, PhD
  • Joe Xie, MD
  • Jiang Tian, PhD
  • David J. Kennedy, PhD
  • Victoria Y. Shilova, PhD
  • Zijian Xie, PhD, Marshall University
  • Jiang Liu, PhD, Marshall University
  • Christopher J. Cooper, MD
  • Deepak Malhotra, MD, PhD
  • Joseph I Shapiro, MD, Marshall University
  • Olga V. Fedorova, PhD
  • Alexei Y. Bagrov, MD, PhD
Document Type
Publication Date

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; PPP

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.


The copy of record is available from the publisher at Copyright © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Citation Information
Haller ST, Yan Y, Drummond CA, et al. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro‐fibrotic signaling. Journal of the American Heart Association 2016;5(10):e004106