Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy.
We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.
Elkareh
Jihad
J
Department of Medicine, University of Toledo College of Medicine, 3120 Glendale Ave, Toledo, OH 43614-5809, USA.
Kennedy
David J
DJ
Yashaswi
Belvadi
B
Vetteth
Sandeep
S
Shidyak
Amjad
A
Kim
Eric G R
EG
Smaili
Sleiman
S
Periyasamy
Sankaridrug M
SM
Hariri
Imad M
IM
Fedorova
Larisa
L
Liu
Jiang
J
Wu
Liang
L
Kahaleh
M Bashar
MB
Xie
Zijian
Z
Malhotra
Deepak
D
Fedorova
Olga V
OV
Kashkin
Vladimir A
VA
Bagrov
Alexei Y
AY
Shapiro
Joseph I
JI
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000503:physiopathology; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014511:Uremia / Q000150:complications*
D002018:Bufanolides; D016212:Transforming Growth Factor beta; C093896:marinobufagenin; D003094:Collagen; D000254:Sodium-Potassium-Exchanging ATPase