Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy

Abstract

The cardiotonic steroid marinobufagenin (MBG) has been implicated in the pathogenesis of experimental uremic cardiomyopathy, which is characterized by progressive cardiac fibrosis. We examined whether the transcription factor Friend leukemia integration-1 (Fli-1) might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice; both developed increased cardiac collagen expression and fibrosis after 5/6 nephrectomy. There was a strong inverse relationship between the expressions of Fli-1 and procollagen in primary culture of rat cardiac and human dermal fibroblasts as well as a cell line derived from renal fibroblasts and MBG-induced decreases in nuclear Fli-1 as well as increases in procollagen-1 expression in these cells. Transfection of a Fli-1 expression vector prevented increased procollagen-1 expression from MBG. MBG exposure induced a rapid translocation of the δ-isoform of protein kinase C (PKCδ) to the nucleus. This translocation was prevented by pharmacological inhibition of phospholipase C, and MBG-induced increases in procollagen-1 expression were prevented with a PKCδ- but not a PKCα-specific inhibitor. Finally, immunoprecipitation studies strongly suggest that MBG induced phosphorylation of Fli-1. We feel these data support a causal relationship with MBG-induced translocation of PKCδ, which results in phosphorylation of as well as decreases in nuclear Fli-1 expression, which, in turn, leads to increases in collagen production. Should these findings be confirmed, we speculate that this pathway may represent a therapeutic target for uremic cardiomyopathy as well as other conditions associated with excessive fibrosis.

Identify potential chronic heart failure related transcription factors by network analysis

“…Fli-1 might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice (Elkareh et al, 2009).…”

Cardiotonic Steroids and Cardiac Fibrosis

“…MBG was seen to induce decreases in Fli-1 expression in cardiac and renal fibroblasts, which was dependent on the nuclear translocation of PKC delta from the cytoplasm. This translocation seems to be necessary for the phosphorylation and degradation of the Fli-1 (Elkareh, Periyasamy et al 2009). This is illustrated in figure 3.…”

“…T h i s p r o b a b l y is the explanation for how the signal transduction is eventually terminated. (Tian, Liu et al 2003;Liu, Liang et al 2005;Yuan, Cai et al 2005;Pierre, Yang et al 2007;Chen, Cai et al 2008;Elkareh, Periyasamy et al 2009). This signaling pathway may link to Bricker's concept of CTS as a natriuretic hormone.…”

Research Progress of Marinobufagenin and Salt-Sensitive Hypertension

“…Studies have found that MBG activated pre-fibrotic signal, which could activate various signaling pathways and EGFR signals by inhibiting NKA, leaded to degeneration of the left ventricular muscle fli-1 and inducing collagen -1 synthesis (Elkareh et al, 2009;Liu et al, 2012;Xie et al, 2013). Study found myocardial fibrosis and siginificant elevation of MBG level in rats with a minipump for infusing MBG and rats had uremia myocarditis (Elkareh et al, 2007).…”

“…Although in the short term, the effect of MBG might balance the high salt load and slow the elevation of blood pressure (Mou et al, 2014), the vasoconstrictive effected by inhibiting NKA may be the long-term response of MBG. In addition, Dietary sodium restriction did not reduce level of plasma MBG (Jablonski et al, 2013).Studies have found that MBG activated pre-fibrotic signal, which could activate various signaling pathways and EGFR signals by inhibiting NKA, leaded to degeneration of the left ventricular muscle fli-1 and inducing collagen -1 synthesis (Elkareh et al, 2009;Liu et al, 2012;Xie et al, 2013). Study found myocardial fibrosis and siginificant elevation of MBG level in rats with a minipump for infusing MBG and rats had uremia myocarditis (Elkareh et al, 2007).…”