Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.
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.
University of Toledo College of Medicine and Life Sciences, Toledo, OH steven.haller@utoledo.edu.
Steven T
ST
Haller
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
Yanling
Y
Yan
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
Christopher A
CA
Drummond
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
Joe
J
Xie
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
Jiang
J
Tian
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
David J
DJ
Kennedy
Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD.
Victoria Y
VY
Shilova
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
Zijian
Z
Xie
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
Jiang
J
Liu
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
Christopher J
CJ
Cooper
University of Toledo College of Medicine and Life Sciences, Toledo, OH.
Deepak
D
Malhotra
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
Joseph I
JI
Shapiro
Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD.
Olga V
OV
Fedorova
Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD.
Alexei Y
AY
Bagrov
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002018:Bufanolides / Q000378:metabolism / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014511:Uremia / Q000378:metabolism / Q000473:pathology*
D002018:Bufanolides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C093896:marinobufagenin; D000254:Sodium-Potassium-Exchanging ATPase; D020123:Sirolimus
cardiac fibrosis; cardiomyopathy; cardiovascular diseases; fibrosis; heart failure
Basic Clin Pharmacol Toxicol. 2007 Jun;100(6):392-7
17516993
J Hypertens. 2006 Aug;24(8):1663-70
16877971
J Am Soc Nephrol. 2006 May;17(5):1395-404
16597691
Circ Cardiovasc Genet. 2015 Oct;8(5):736-45
26374826
J Biol Chem. 2001 Jun 15;276(24):20839-48
11278621
J Histochem Cytochem. 1985 Aug;33(8):737-43
2410480
Am J Physiol Renal Physiol. 2010 Jan;298(1):F142-9
19846571
Hypertension. 2009 Dec;54(6):1313-20
19884563
J Biol Chem. 2012 May 11;287(20):16390-8
22451662
Am J Physiol Heart Circ Physiol. 2014 Jun 15;306(12):H1631-43
24748592
Am J Hypertens. 2012 Jun;25(6):690-6
22378033
Circulation. 2003 Oct 28;108(17):2154-69
14581387
J Hypertens. 1999 Aug;17(8):1179-87
10466474
Kidney Int. 2002 Oct;62(4):1402-7
12234312
Arthritis Rheum. 2006 Jul;54(7):2271-9
16802366
J Hypertens. 2008 Dec;26(12):2414-25
19008721
J Am Soc Nephrol. 2010 Mar;21(3):489-97
20075061
Nucleic Acids Res. 2005 Mar 01;33(4):1337-51
15741186
Kidney Int. 2015 Sep;88(3):515-27
25970154
Hypertension. 2000 Sep;36(3):442-8
10988279
Urology. 2003 Oct;62(4):750-4
14550466
Biom J. 2008 Jun;50(3):346-63
18481363
J Biol Chem. 2006 Nov 3;281(44):33045-52
16914544
Hypertension. 2006 Mar;47(3):488-95
16446397
N Engl J Med. 1988 Feb 25;318(8):518-9
3340135
J Hypertens. 2005 Apr;23(4):835-42
15775789
Am J Physiol Renal Physiol. 2008 Feb;294(2):F450-4
18032546
J Hypertens. 2011 Apr;29(4):769-76
21330936
Biochem Pharmacol. 1969 Aug;18(8):1797-802
5811615
Cell Mol Biol (Noisy-le-grand). 2006 Dec 30;52(8):19-23
17535731
J Hypertens. 2010 Feb;28(2):361-6
19927009
Am J Physiol Renal Physiol. 2009 May;296(5):F1219-26
19261738
J Biol Chem. 2009 Feb 13;284(7):4052-61
19074768
Cardiorenal Med. 2015 Oct;5(4):254-66
26648942
Kidney Int. 2009 Apr;75(8):800-8
19165175
Am J Nephrol. 2005 Sep-Oct;25(5):520-8
16179779
Pharmacol Rev. 2009 Mar;61(1):9-38
19325075
Reprod Sci. 2012 Dec;19(12):1260-7
22649120
Hypertension. 2007 Jan;49(1):215-24
17145984
J Am Soc Nephrol. 2009 Dec;20(12):2493-502
19875810
J Biol Chem. 2004 May 28;279(22):23166-75
15047702
Transplant Proc. 2008 Dec;40(10 Suppl):S5-8
19100909
Curr Biol. 2004 Jul 27;14(14):1296-302
15268862
J Hypertens (Los Angel). 2013 Jan 31;2:null
24404431
Nephrol Dial Transplant. 2011 Sep;26(9):2912-9
21292813
J Mol Cell Cardiol. 1994 Jul;26(7):809-20
7966349