Artery Research

Volume 7, Issue 3-4, September 2013, Pages 169 - 169

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

Authors
O.V. Fedorova, V. Shilova, V. Zernetkina, Y. Zhang, E. Lehrmann, K.G. Becker, E.G. Lakatta, A.Y. Bagrov
National Institute on Aging, NIH, Baltimore, United States
Available Online 11 November 2013.
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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Journal
Artery Research
Volume-Issue
7 - 3-4
Pages
169 - 169
Publication Date
2013/11/11
ISSN (Online)
1876-4401
ISSN (Print)
1872-9312
DOI
10.1016/j.artres.2013.10.027How to use a DOI?
Open Access
This is an open access article distributed under the CC BY-NC license.

Cite this article

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  -