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

J Am Heart Assoc. 2016 Sep 30;5(10):e004106. doi: 10.1161/JAHA.116.004106.

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-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.

Keywords: cardiac fibrosis; cardiomyopathy; cardiovascular diseases; fibrosis; heart failure.

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Bufanolides / metabolism
  • Bufanolides / pharmacology*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology*
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Heart / drug effects*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Male
  • Myocardium / pathology*
  • Nephrectomy
  • Rats
  • Rats, Sprague-Dawley
  • Sirolimus / pharmacology*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Uremia / metabolism
  • Uremia / pathology*

Substances

  • Bufanolides
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • marinobufagenin
  • Sodium-Potassium-Exchanging ATPase
  • Sirolimus