5.4 A MONOCLONAL ANTIBODY TO AN ENDOGENOUS NA/K-ATPASE LIGAND, MARINOBUFAGENIN, REVERSES EXPRESSION OF PRO-FIBROTIC GENES AND REDUCES CARDIOVASCULAR FIBROSIS IN AGED RATS

DOI

10.1016/j.artres.2013.10.027How to use a DOI?

Abstract

Cardiovascular fibrosis is a hallmark of aging. We had previously demonstrated, that a steroidal endogenous Na/K-ATPase inhibitor, marinobufagenin (MBG), plays a central role in cardiac fibrosis occurring in the context of experimental uremic cardiomyopathy (Hypertension 2007;49:215–24) via participation in Fli-1-dependent pro-fibrotic signaling. Here, we hypothesized, that MBG is implicated in aging-associated fibrosis, and that immunoneutralization of MBG in old rats will reverse pro-fibrotic signalling.

To test our hypothesis, we measured plasma MBG in young (3-mo old) and aged (24-mo old) Sprague-Dawley rats, and in aged rats determined the effect of immunoneutralization of MBG on the expression of pro-fibrotic genes in left ventricular (LV) myocardium. One week following a single administration to aged rats of an anti-MBG monoclonal antibody (n = 6) or vehicle (n = 6), the expression of genes and levels of proteins implicated in pro-fibrotic signalling (qPCR) were assessed in LV myocardium.

Plasma MBG levels were elevated 2-fold (p < 0.05) in old vs. young rats, and was accompanied by up-regulation of genes implicated in TGFβ-signaling: TGFβ1 – 3-fold, CTGF1 – 6-fold, SMAD3 – 2-fold, collagen-1 – 2.6 fold. Expression of these genes was significantly suppresses following immunoneutralization of MBG in aged rats, although their expression remained higher than in young controls. The expression of a nuclear transcription factor Fli-1, a negative regulator of collagen-1 synthesis, was reduced by 3-fold in old vs. young rats, and anti-MBG antibody restored levels of Fli-1 in old rats to the level in young controls.

Thus, immunoneutralization of MBG produces an anti-remodeling effect associated with down-regulation of genes implicated in TGFβ-induced fibrosis. The age-associated increase in MBG participates in pro-fibrotic signaling linked to advancing age, and cross-talk between TGFβ-dependent and Fli-1-dependent pro-fibrotic pathways underlies this MBG effect.

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TY  - JOUR
AU  - O.V. Fedorova
AU  - V. Shilova
AU  - V. Zernetkina
AU  - Y. Zhang
AU  - E. Lehrmann
AU  - K.G. Becker
AU  - E.G. Lakatta
AU  - A.Y. Bagrov
PY  - 2013
DA  - 2013/11/11
TI  - 5.4 A MONOCLONAL ANTIBODY TO AN ENDOGENOUS NA/K-ATPASE LIGAND, MARINOBUFAGENIN, REVERSES EXPRESSION OF PRO-FIBROTIC GENES AND REDUCES CARDIOVASCULAR FIBROSIS IN AGED RATS
JO  - Artery Research
SP  - 169
EP  - 169
VL  - 7
IS  - 3-4
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2013.10.027
DO  - 10.1016/j.artres.2013.10.027
ID  - Fedorova2013
ER  -