Published Online
on December 4, 2006

A more recent version of this article appeared on January 1, 2007

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Submitted on September 29, 2006
Revised on October 17, 2006

Marinobufagenin Stimulates Fibroblast Collagen Production and Causes Fibrosis in Experimental Uremic Cardiomyopathy

Jihad Elkareh; David J. Kennedy; Belvadi Yashaswi; Sandeep Vetteth; Amjad Shidyak; Eric G.R. Kim; Sleiman Smaili; Sankaridrug M. Periyasamy; Imad M. Hariri; Larisa Fedorova; Jiang Liu; Liang Wu; M. Bashar Kahaleh; Zijian Xie; Deepak Malhotra; Olga V. Fedorova; Vladimir A. Kashkin; Alexei Y. Bagrov; and Joseph I. Shapiro^*

From the Departments of Medicine and Pharmacology (J.E., D.J.K., B.Y., S.V., A.S., E.G.R.K., S.S., S.M.P., I.M.H., L.F., J.L., L.W., M.B.K., Z.X., D.M., J.I.S.), University of Toledo College of Medicine, Ohio; and the Laboratory of Cardiovascular Science O.V.F., V.A.K., A.Y.B.), National Institute on Aging, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: joseph.shapiro{at}utoledo.edu.

Abstract--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.

Key words: cardiomyopathy • renal failure • transforming growth factor (TGF) • cardiotonic steroids • reactive oxygen species • fibrosis

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